Publications by authors named "Trever G Bivona"

112 Publications

AXL and error-prone DNA replication confer drug resistance and offer strategies to treat EGFR-mutant lung cancer.

Cancer Discov 2022 Jul 27. Epub 2022 Jul 27.

Broad Institute of MIT and Harvard, United States.

Anti-cancer therapies have been limited by emergence of mutations and other adaptations. In bacteria, antibiotics activate the SOS response, which mobilizes error-prone factors that allow for continuous replication at the cost of mutagenesis. We investigated whether treatment of lung cancer with EGFR inhibitors (EGFRi) similarly engages hypermutators. In cycling drug-tolerant persister (DTP) cells and in EGFRi-treated patients presenting residual disease we observed upregulation of GAS6, while ablation of GAS6's receptor, AXL, eradicated resistance. Reciprocally, AXL overexpression enhanced DTP survival and accelerated the emergence of T790M, an EGFR mutation typical to resistant cells. Mechanistically, AXL induces low-fidelity DNA polymerases and activates their organizer, RAD18, by promoting neddylation. Metabolomics uncovered another hypermutator, AXL-driven activation of MYC and increased purine synthesis that is unbalanced by pyrimidines. Aligning anti-AXL combination treatments with the transition from DTPs to resistant cells cured patient-derived xenografts. Hence, similar to bacteria, tumors tolerate therapy by engaging pharmacologically targetable endogenous mutators.
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http://dx.doi.org/10.1158/2159-8290.CD-22-0111DOI Listing
July 2022

Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer.

J Clin Invest 2022 07;132(13)

Department of Medicine and.

Molecularly targeted cancer therapy has improved outcomes for patients with cancer with targetable oncoproteins, such as mutant EGFR in lung cancer. Yet, the long-term survival of these patients remains limited, because treatment responses are typically incomplete. One potential explanation for the lack of complete and durable responses is that oncogene-driven cancers with activating mutations of EGFR often harbor additional co-occurring genetic alterations. This hypothesis remains untested for most genetic alterations that co-occur with mutant EGFR. Here, we report the functional impact of inactivating genetic alterations of the mRNA splicing factor RNA-binding motif 10 (RBM10) that co-occur with mutant EGFR. RBM10 deficiency decreased EGFR inhibitor efficacy in patient-derived EGFR-mutant tumor models. RBM10 modulated mRNA alternative splicing of the mitochondrial apoptotic regulator Bcl-x to regulate tumor cell apoptosis during treatment. Genetic inactivation of RBM10 diminished EGFR inhibitor-mediated apoptosis by decreasing the ratio of (proapoptotic) Bcl-xS to (antiapoptotic) Bcl-xL isoforms of Bcl-x. RBM10 deficiency was a biomarker of poor response to EGFR inhibitor treatment in clinical samples. Coinhibition of Bcl-xL and mutant EGFR overcame the resistance induced by RBM10 deficiency. This study sheds light on the role of co-occurring genetic alterations and on the effect of splicing factor deficiency on the modulation of sensitivity to targeted kinase inhibitor cancer therapy.
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http://dx.doi.org/10.1172/JCI145099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9246391PMC
July 2022

Lineage tracing reveals the phylodynamics, plasticity, and paths of tumor evolution.

Cell 2022 05 5;185(11):1905-1923.e25. Epub 2022 May 5.

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address:

Tumor evolution is driven by the progressive acquisition of genetic and epigenetic alterations that enable uncontrolled growth and expansion to neighboring and distal tissues. The study of phylogenetic relationships between cancer cells provides key insights into these processes. Here, we introduced an evolving lineage-tracing system with a single-cell RNA-seq readout into a mouse model of Kras;Trp53(KP)-driven lung adenocarcinoma and tracked tumor evolution from single-transformed cells to metastatic tumors at unprecedented resolution. We found that the loss of the initial, stable alveolar-type2-like state was accompanied by a transient increase in plasticity. This was followed by the adoption of distinct transcriptional programs that enable rapid expansion and, ultimately, clonal sweep of stable subclones capable of metastasizing. Finally, tumors develop through stereotypical evolutionary trajectories, and perturbing additional tumor suppressors accelerates progression by creating novel trajectories. Our study elucidates the hierarchical nature of tumor evolution and, more broadly, enables in-depth studies of tumor progression.
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http://dx.doi.org/10.1016/j.cell.2022.04.015DOI Listing
May 2022

Small-molecule targeted therapies induce dependence on DNA double-strand break repair in residual tumor cells.

Sci Transl Med 2022 03 30;14(638):eabc7480. Epub 2022 Mar 30.

Department of Pharmacology and Cancer Biology and Duke Cancer Institute, Duke University, Durham, NC 27710, USA.

Residual cancer cells that survive drug treatments with targeted therapies act as a reservoir from which eventual resistant disease emerges. Although there is great interest in therapeutically targeting residual cells, efforts are hampered by our limited knowledge of the vulnerabilities existing in this cell state. Here, we report that diverse oncogene-targeted therapies, including inhibitors of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), KRAS, and BRAF, induce DNA double-strand breaks and, consequently, ataxia-telangiectasia mutated (ATM)-dependent DNA repair in oncogene-matched residual tumor cells. This DNA damage response, observed in cell lines, mouse xenograft models, and human patients, is driven by a pathway involving the activation of caspases 3 and 7 and the downstream caspase-activated deoxyribonuclease (CAD). CAD is, in turn, activated through caspase-mediated degradation of its endogenous inhibitor, ICAD. In models of mutant non-small cell lung cancer (NSCLC), tumor cells that survive treatment with small-molecule EGFR-targeted therapies are thus synthetically dependent on ATM, and combined treatment with an ATM kinase inhibitor eradicates these cells in vivo. This led to more penetrant and durable responses in mutant NSCLC mouse xenograft models, including those derived from both established cell lines and patient tumors. Last, we found that rare patients with mutant NSCLC harboring co-occurring, loss-of-function mutations in exhibit extended progression-free survival on first generation EGFR inhibitor therapy relative to patients with mutant NSCLC lacking deleterious mutations. Together, these findings establish a rationale for the mechanism-based integration of ATM inhibitors alongside existing targeted therapies.
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http://dx.doi.org/10.1126/scitranslmed.abc7480DOI Listing
March 2022

Understanding Drug Sensitivity and Tackling Resistance in Cancer.

Cancer Res 2022 04;82(8):1448-1460

Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.

Decades of research into the molecular mechanisms of cancer and the development of novel therapeutics have yielded a number of remarkable successes. However, our ability to broadly assign effective, rationally targeted therapies in a personalized manner remains elusive for many patients, and drug resistance persists as a major problem. This is in part due to the well-documented heterogeneity of cancer, including the diversity of tumor cell lineages and cell states, the spectrum of somatic mutations, the complexity of microenvironments, and immune-suppressive features and immune repertoires, which collectively require numerous different therapeutic approaches. Here, we describe a framework to understand the types and biological causes of resistance, providing translational opportunities to tackle drug resistance by rational therapeutic strategies.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-3695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9018544PMC
April 2022

Remodeling of the tumor/tumor microenvironment ecosystem during KRAS G12C inhibitor clinical resistance in lung cancer.

J Clin Invest 2022 02;132(4)

Department of Medicine.

KRAS G12C inhibitors such as sotorasib and adagrasib are often effective in KRAS G12C-driven non-small cell lung cancer (NSCLC) patients. However, acquired resistance limits long-term patient survival. In this issue of the JCI, Tsai et al. present a comprehensive genetic analysis of multiple tumors with acquired sotorasib resistance obtained through an autopsy of a patient with KRAS G12C-mutant NSCLC. This analysis of pre- and posttreatment tumors uncovered cancer cell-intrinsic and -extrinsic features of resistance, including reactivation of KRAS-mediated signaling, reprogramming of metabolism, epithelial-mesenchymal transition, and tumor microenvironment changes. This elegant study demonstrates the multifaceted nature of KRAS G12C inhibitor clinical resistance and potential avenues to overcome resistance.
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http://dx.doi.org/10.1172/JCI156891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8843703PMC
February 2022

Inhibition of SHP2 as an approach to block RAS-driven cancers.

Adv Cancer Res 2022 3;153:205-236. Epub 2021 Aug 3.

Department of Medicine, Division of Hematology and Oncology, and The Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA, United States. Electronic address:

The non-receptor protein tyrosine phosphatase SHP2 (encoded by PTPN11) is a critical component of RAS/MAPK signaling by acting upstream of RAS to promote oncogenic signaling and tumor growth. Over three decades, SHP2 was considered "undruggable" because enzymatic active-site inhibitors generally showed off-target inhibition of other proteins and low membrane permeability. More recently, allosteric SHP2 inhibitors with striking inhibitory potency have been developed. These small molecules effectively block the signal transduction between receptor tyrosine kinases (RTKs) and RAS/MAPK signaling and show efficacy in preclinical cancer models. Moreover, clinical evaluation of these allosteric SHP2 inhibitors is ongoing. RAS proteins which harbor transforming properties by gain-of-function mutations are present in various cancer types. While inhibitors of KRASG12C show early clinical promise, resistance remains a challenge and other forms of oncogenic RAS remain to be selectively inhibited. Here, we summarize the role of SHP2 in RAS-driven cancers and the therapeutic potential of allosteric SHP2 inhibitors as a strategy to block RAS-driven cancers.
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http://dx.doi.org/10.1016/bs.acr.2021.07.002DOI Listing
March 2022

Digital multiplexed analysis of circular RNAs in FFPE and fresh non-small cell lung cancer specimens.

Mol Oncol 2022 06 10;16(12):2367-2383. Epub 2022 Feb 10.

Germans Trias I Pujol Research Institute, Badalona, Spain.

Although many studies highlight the implication of circular RNAs (circRNAs) in carcinogenesis and tumor progression, their potential as cancer biomarkers has not yet been fully explored in the clinic due to the limitations of current quantification methods. Here, we report the use of the nCounter platform as a valid technology for the analysis of circRNA expression patterns in non-small cell lung cancer (NSCLC) specimens. Under this context, our custom-made circRNA panel was able to detect circRNA expression both in NSCLC cells and formalin-fixed paraffin-embedded (FFPE) tissues. CircFUT8 was overexpressed in NSCLC, contrasting with circEPB41L2, circBNC2, and circSOX13 downregulation even at the early stages of the disease. Machine learning (ML) approaches from different paradigms allowed discrimination of NSCLC from nontumor controls (NTCs) with an 8-circRNA signature. An additional 4-circRNA signature was able to classify early-stage NSCLC samples from NTC, reaching a maximum area under the ROC curve (AUC) of 0.981. Our results not only present two circRNA signatures with diagnosis potential but also introduce nCounter processing following ML as a feasible protocol for the study and development of circRNA signatures for NSCLC.
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http://dx.doi.org/10.1002/1878-0261.13182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9208080PMC
June 2022

Evolution of metastasis: new tools and insights.

Trends Cancer 2022 02 3;8(2):98-109. Epub 2021 Dec 3.

Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. Electronic address:

Metastasis is an evolutionary process occurring across multiple organs and timescales. Due to its continuous and dynamic nature, this multifaceted process has been challenging to investigate and remains incompletely understood, in part due to the lack of tools capable of probing genomic evolution at high enough resolution. However, technological advances in genetic sequencing and editing have provided new and powerful methods to refine our understanding of the complex series of events that lead to metastatic dissemination. In this review, we summarize the latest genetic and lineage-tracing approaches developed to unravel the genetic evolution of metastasis. The findings that have emerged have enhanced our comprehension of the mechanistic trajectories and timescales of metastasis and could provide new strategies for therapy.
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http://dx.doi.org/10.1016/j.trecan.2021.11.002DOI Listing
February 2022

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids.

J Vis Exp 2021 11 22(177). Epub 2021 Nov 22.

Department of Medicine, University of California, San Francisco; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco; Department of Cellular and Molecular Pharmacology, University of California, San Francisco;

Novel 3D cancer organoid cultures derived from clinical patient specimens represent an important model system to evaluate intratumor heterogeneity and treatment response to targeted inhibitors in cancer. Pioneering work in gastrointestinal and pancreatic cancers has highlighted the promise of patient-derived organoids (PDOs) as a patient-proximate culture system, with an increasing number of models emerging. Similarly, work in other cancer types has focused on establishing organoid models and optimizing culture protocols. Notably, 3D cancer organoid models maintain the genetic complexity of original tumor specimens and thus translate tumor-derived sequencing data into treatment with genetically informed targeted therapies in an experimental setting. Further, PDOs might foster the evaluation of rational combination treatments to overcome resistance-associated adaptation of tumors in the future. The latter focuses on intense research efforts in non-small-cell lung cancer (NSCLC), as resistance development ultimately limits the treatment success of targeted inhibitors. An early assessment of therapeutically targetable mechanisms using NSCLC PDOs could help inform rational combination treatments. This manuscript describes a standardized protocol for the cell culture plate-based assessment of drug sensitivities to targeted inhibitors in NSCLC-derived 3D PDOs, with potential adaptability to combinational treatments and other treatment modalities.
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http://dx.doi.org/10.3791/63039DOI Listing
November 2021

DDX56 modulates post-transcriptional Wnt signaling through miRNAs and is associated with early recurrence in squamous cell lung carcinoma.

Mol Cancer 2021 08 26;20(1):108. Epub 2021 Aug 26.

Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsløwsvej 25, 5000, Odense C, Denmark.

Background: Early recurrence is a major obstacle to prolonged postoperative survival in squamous cell lung carcinoma (SqCLC). The molecular mechanisms underlying early SqCLC recurrence remain unclear, and effective prognostic biomarkers for predicting early recurrence are needed.

Methods: We analyzed primary tumor samples of 20 SqCLC patients using quantitative proteomics to identify differentially-expressed proteins in patients who experienced early versus late disease recurrence. The expression and prognostic significance of DDX56 was evaluated using a SqCLC tumor tissue microarray and further verified using different online databases. We performed in vitro and in vivo experiments to obtain detailed molecular insight into the functional role of DDX56 in SqCLC.

Results: We found that DDX56 exhibited increased expression in tumors of patients who experienced early versus late disease recurrence. Increased DDX56 expression in SqCLC tumors was subsequently confirmed as an independent prognostic factor of poor recurrence-free survival in independent SqCLC cohorts. Functionally, DDX56 promotes SqCLC cell growth and migration in vitro, and xenograft tumor progression in vivo. Mechanistically, DDX56 post-transcriptionally promotes expression of multiple Wnt signaling pathway-related genes, including CTNNB1, WNT2B, and represses a subset of miRNAs, including miR-378a-3p, a known suppressor of Wnt signaling. Detailed analysis revealed that DDX56 facilitated degradation of primary miR-378a, leading to down-regulation of mature miR-378a-3p and thus derepression of the target gene WNT2B.

Conclusion: We identified DDX56 as a novel independent prognostic biomarker that exerts its oncogenic effects through miRNA-mediated post-transcriptional regulation of Wnt signaling genes to promote early SqCLC recurrence. DDX56 may assist in identifying SqCLC patients at increased risk of early recurrence and who could benefit from Wnt signaling-targeted therapies.
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http://dx.doi.org/10.1186/s12943-021-01403-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393456PMC
August 2021

Targeting AXL in NSCLC.

Lung Cancer (Auckl) 2021 10;12:67-79. Epub 2021 Aug 10.

Department of Medicine, University of California, San Francisco, CA, USA.

State-of-the-art cancer precision medicine approaches involve targeted inactivation of chemically and immunologically addressable vulnerabilities that often yield impressive initial anti-tumor responses in patients. Nonetheless, these responses are overshadowed by therapy resistance that follows. AXL, a receptor tyrosine kinase with bona fide oncogenic capacity, has been associated with the emergence of resistance in an array of cancers with varying pathophysiology and cellular origins, including in non-small-cell lung cancers (NSCLCs). Here in this review, we summarize AXL biology during normal homeostasis, oncogenic development and therapy resistance with a focus on NSCLC. In the context of NSCLC therapy resistance, we delineate AXL's role in mediating resistance to tyrosine kinase inhibitors (TKIs) deployed against epidermal growth factor receptor (EGFR) as well as other notable oncogenes and to chemotherapeutics. We also discuss the current understanding of AXL's role in mediating cell-biological variables that function as important modifiers of therapy resistance such as epithelial to mesenchymal transition (EMT), the tumor microenvironment and tumor heterogeneity. We also catalog and discuss a set of effective pharmacologic tools that are emerging to strategically perturb AXL mediated resistance programs in NSCLC. Finally, we enumerate ongoing and future exciting precision medicine approaches targeting AXL as well as challenges in this regard. We highlight that a holistic understanding of AXL biology in NSCLC may allow us to predict and improve targeted therapeutic strategies, such as through polytherapy approaches, potentially against a broad spectrum of NSCLC sub-types to forestall tumor evolution and drug resistance.
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http://dx.doi.org/10.2147/LCTT.S305484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364399PMC
August 2021

Exocyst protein subnetworks integrate Hippo and mTOR signaling to promote virus detection and cancer.

Cell Rep 2021 08;36(5):109491

Department of Medicine, University of California, San Francisco, 600 16th Street, San Francisco, CA 94158, USA; UCSF Helen Diller Comprehensive Cancer Center, University of California, San Francisco, 600 16th Street, San Francisco, CA 94158, USA. Electronic address:

The exocyst is an evolutionarily conserved protein complex that regulates vesicular trafficking and scaffolds signal transduction. Key upstream components of the exocyst include monomeric RAL GTPases, which help mount cell-autonomous responses to trophic and immunogenic signals. Here, we present a quantitative proteomics-based characterization of dynamic and signal-dependent exocyst protein interactomes. Under viral infection, an Exo84 exocyst subcomplex assembles the immune kinase Protein Kinase R (PKR) together with the Hippo kinase Macrophage Stimulating 1 (MST1). PKR phosphorylates MST1 to activate Hippo signaling and inactivate Yes Associated Protein 1 (YAP1). By contrast, a Sec5 exocyst subcomplex recruits another immune kinase, TANK binding kinase 1 (TBK1), which interacted with and activated mammalian target of rapamycin (mTOR). RALB was necessary and sufficient for induction of Hippo and mTOR signaling through parallel exocyst subcomplex engagement, supporting the cellular response to virus infection and oncogenic signaling. This study highlights RALB-exocyst signaling subcomplexes as mechanisms for the integrated engagement of Hippo and mTOR signaling in cells challenged by viral pathogens or oncogenic signaling.
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http://dx.doi.org/10.1016/j.celrep.2021.109491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383154PMC
August 2021

Stepwise evolution of therapy resistance in AML.

Cancer Cell 2021 07 24;39(7):904-906. Epub 2021 Jun 24.

Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. Electronic address:

Relapse of AML patients to FLT3i treatment is the result of a long-term and stepwise process leading to resistance, whereby residual cancer cells initially survive and subsequently expand. Here, Joshi et al. use a multifaceted approach to characterize how microenvironment-driven early resistance to gilteritinib evolves into mutation-driven late resistance.
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http://dx.doi.org/10.1016/j.ccell.2021.06.004DOI Listing
July 2021

Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules.

Cell 2021 05 12;184(10):2649-2664.e18. Epub 2021 Apr 12.

Department of Medicine, Division of Hematology and Oncology, UCSF, San Francisco, CA 94143, USA. Electronic address:

Receptor tyrosine kinase (RTK)-mediated activation of downstream effector pathways such as the RAS GTPase/MAP kinase (MAPK) signaling cascade is thought to occur exclusively from lipid membrane compartments in mammalian cells. Here, we uncover a membraneless, protein granule-based subcellular structure that can organize RTK/RAS/MAPK signaling in cancer. Chimeric (fusion) oncoproteins involving certain RTKs including ALK and RET undergo de novo higher-order assembly into membraneless cytoplasmic protein granules that actively signal. These pathogenic biomolecular condensates locally concentrate the RAS activating complex GRB2/SOS1 and activate RAS in a lipid membrane-independent manner. RTK protein granule formation is critical for oncogenic RAS/MAPK signaling output in these cells. We identify a set of protein granule components and establish structural rules that define the formation of membraneless protein granules by RTK oncoproteins. Our findings reveal membraneless, higher-order cytoplasmic protein assembly as a distinct subcellular platform for organizing oncogenic RTK and RAS signaling.
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http://dx.doi.org/10.1016/j.cell.2021.03.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127962PMC
May 2021

Single-cell lineages reveal the rates, routes, and drivers of metastasis in cancer xenografts.

Science 2021 02 21;371(6532). Epub 2021 Jan 21.

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.

Detailed phylogenies of tumor populations can recount the history and chronology of critical events during cancer progression, such as metastatic dissemination. We applied a Cas9-based, single-cell lineage tracer to study the rates, routes, and drivers of metastasis in a lung cancer xenograft mouse model. We report deeply resolved phylogenies for tens of thousands of cancer cells traced over months of growth and dissemination. This revealed stark heterogeneity in metastatic capacity, arising from preexisting and heritable differences in gene expression. We demonstrate that these identified genes can drive invasiveness and uncovered an unanticipated suppressive role for We also show that metastases disseminated via multidirectional tissue routes and complex seeding topologies. Overall, we demonstrate the power of tracing cancer progression at subclonal resolution and vast scale.
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http://dx.doi.org/10.1126/science.abc1944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983364PMC
February 2021

Allosteric SHP2 inhibitors in cancer: Targeting the intersection of RAS, resistance, and the immune microenvironment.

Curr Opin Chem Biol 2021 06 6;62:1-12. Epub 2021 Jan 6.

Department of Medicine, University of California, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA. Electronic address:

The nonreceptor protein tyrosine phosphatase SHP2 (encoded by PTPN11) integrates growth and differentiation signals from receptor tyrosine kinases (RTKs) into the RAS/mitogen-activated protein kinase (MAPK) cascade. Considered 'undruggable' over three decades, SHP2 is now a potentially druggable target with the advent of allosteric SHP2 inhibitors. These agents hold promise for improving patient outcomes, showing efficacy in preclinical cancer models, where SHP2 is critical for either oncogenic signaling or resistance to current targeted agents. SHP2 inhibition may also produce immunomodulatory effects in certain tumor microenvironment cells to help cultivate antitumor immune responses. The first generation of allosteric SHP2 inhibitors is under clinical evaluation to determine safety, appropriate tolerability management, and antitumor efficacy, investigations that will dictate future clinical applications.
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http://dx.doi.org/10.1016/j.cbpa.2020.11.007DOI Listing
June 2021

Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis.

Oncogenesis 2020 Nov 19;9(11):102. Epub 2020 Nov 19.

Laboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Lung cancer mortality largely results from metastasis. Despite curative surgery many patients with early-stage non-small cell lung cancer ultimately succumb to metastatic relapse. Current risk reduction strategies based on cytotoxic chemotherapy and radiation have only modest activity. Against this background, we functionally screened for novel metastasis modulators using a barcoded shRNA library and an orthotopic lung cancer model. We identified aryl hydrocarbon receptor (AHR), a sensor of xenobiotic chemicals and transcription factor, as suppressor of lung cancer metastasis. Knockdown of endogenous AHR induces epithelial-mesenchymal transition signatures, increases invasiveness of lung cancer cells in vitro and metastasis formation in vivo. Low intratumoral AHR expression associates with inferior outcome of patients with resected lung adenocarcinomas. Mechanistically, AHR triggers ATF4 signaling and represses matrix metalloproteinase activity, both counteracting metastatic programs. These findings link the xenobiotic defense system with control of lung cancer progression. AHR-regulated pathways are promising targets for innovative anti-metastatic strategies.
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http://dx.doi.org/10.1038/s41389-020-00286-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677369PMC
November 2020

Long non-coding RNA ESCCAL-1 promotes esophageal squamous cell carcinoma by down regulating the negative regulator of APOBEC3G.

Cancer Lett 2020 11 6;493:217-227. Epub 2020 Sep 6.

Translational Medical Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450007, PR China. Electronic address:

The expression of lncRNA ESCCAL-1 is upregulated in esophageal squamous cell carcinoma (ESCC). However, the molecular pathways regulated by ESCCAL-1 in esophageal cancer remain obscure. We found that high expression of the lncRNA ESCCAL-1 in human ESCC tumors correlated with worse clinicopathologic features. Furthermore, depletion of ESCCAL-1 in ESCC models inhibited the cellular processes associated with malignancy, including proliferation, migration and invasion, resistance to apoptosis, and impaired tumor growth in mice. Using a combinatorial approach, we discovered that ESCCAL-1 regulates malignant phenotypes in ESCC by acting as a molecular sponge for miR-590-3p. This interaction prevents miR-590-3p from suppressing APOBEC3G expression. Increased APOBEC3G was also a biomarker of worse clinicopathologic features in human ESCC tumors. Depletion of ESSCAL-1 or APOBEC3G, or overexpression of miR-590-3p resulted in increased apoptosis due to downregulation of the PI3K/Akt signaling. This study demonstrates that the lncRNA ESCCAL-1 promotes malignant features of ESCC by relieving the inhibitory effect of miR-590-3p on APOBEC3G expression and identifies potential biomarkers or therapeutic targets to improve ESCC treatment outcomes.
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http://dx.doi.org/10.1016/j.canlet.2020.09.001DOI Listing
November 2020

Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing.

Cell 2020 09 20;182(5):1232-1251.e22. Epub 2020 Aug 20.

Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.

Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) of metastatic lung cancer was performed using 49 clinical biopsies obtained from 30 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNA-seq of cancer cells illuminated targetable oncogenes beyond those detected clinically. Cancer cells surviving therapy as residual disease (RD) expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitive cell-state transition, whereas those present at on-therapy progressive disease (PD) upregulated kynurenine, plasminogen, and gap-junction pathways. Active T-lymphocytes and decreased macrophages were present at RD and immunosuppressive cell states characterized PD. Biological features revealed by scRNA-seq were biomarkers of clinical outcomes in independent cohorts. This study highlights how therapy-induced adaptation of the multi-cellular ecosystem of metastatic cancer shapes clinical outcomes.
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http://dx.doi.org/10.1016/j.cell.2020.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484178PMC
September 2020

Multi-faceted epigenetic dysregulation of gene expression promotes esophageal squamous cell carcinoma.

Nat Commun 2020 07 22;11(1):3675. Epub 2020 Jul 22.

Department of Medicine, University of California San Francisco, San Francisco, CA, USA.

Epigenetic landscapes can shape physiologic and disease phenotypes. We used integrative, high resolution multi-omics methods to delineate the methylome landscape and characterize the oncogenic drivers of esophageal squamous cell carcinoma (ESCC). We found 98% of CpGs are hypomethylated across the ESCC genome. Hypo-methylated regions are enriched in areas with heterochromatin binding markers (H3K9me3, H3K27me3), while hyper-methylated regions are enriched in polycomb repressive complex (EZH2/SUZ12) recognizing regions. Altered methylation in promoters, enhancers, and gene bodies, as well as in polycomb repressive complex occupancy and CTCF binding sites are associated with cancer-specific gene dysregulation. Epigenetic-mediated activation of non-canonical WNT/β-catenin/MMP signaling and a YY1/lncRNA ESCCAL-1/ribosomal protein network are uncovered and validated as potential novel ESCC driver alterations. This study advances our understanding of how epigenetic landscapes shape cancer pathogenesis and provides a resource for biomarker and target discovery.
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http://dx.doi.org/10.1038/s41467-020-17227-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376194PMC
July 2020

EGFR targeted therapy resistance: current status, challenges, and future outlook.

Authors:
Trever G Bivona

J Thorac Dis 2020 May;12(5):2849-2850

Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.

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http://dx.doi.org/10.21037/jtd.2020.04.08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330318PMC
May 2020

Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations.

J Thorac Oncol 2020 10 13;15(10):1611-1623. Epub 2020 Jun 13.

Division of Hematology and Oncology, University of California San Francisco, San Francisco, California. Electronic address:

Introduction: Approximately 4% of NSCLC harbor BRAF mutations, and approximately 50% of these are non-V600 mutations. Treatment of tumors harboring non-V600 mutations is challenging because of functional heterogeneity and lack of knowledge regarding their clinical significance and response to targeted agents.

Methods: We conducted an integrative analysis of BRAF non-V600 mutations using genomic profiles of BRAF-mutant NSCLC from the Guardant360 database. BRAF mutations were categorized by clonality and class (1 and 2: RAS-independent; 3: RAS-dependent). Cell viability assays were performed in Ba/F3 models. Drug screens were performed in NSCLC cell lines.

Results: A total of 305 unique BRAF mutations were identified. Missense mutations were most common (276, 90%), and 45% were variants of unknown significance. F468S and N581Y were identified as novel activating mutations. Class 1 to 3 mutations had higher clonality than mutations of unknown class (p < 0.01). Three patients were treated with MEK with or without BRAF inhibitors. Patients harboring G469V and D594G mutations did not respond, whereas a patient with the L597R mutation had a durable response. Trametinib with or without dabrafenib, LXH254, and lifirafenib had more potent inhibition of BRAF non-V600-mutant NSCLC cell lines than other MEK, BRAF, and ERK inhibitors, comparable with the inhibition of BRAF V600E cell line.

Conclusions: In BRAF-mutant NSCLC, clonality is higher in known functional mutations and may allow identification of variants of unknown significance that are more likely to be oncogenic drivers. Our data indicate that certain non-V600 mutations are responsive to MEK and BRAF inhibitors. This integration of genomic profiling and drug sensitivity may guide the treatment for BRAF-mutant NSCLC.
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http://dx.doi.org/10.1016/j.jtho.2020.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529990PMC
October 2020

Overcoming the challenges of cancer drug resistance through bacterial-mediated therapy.

Chronic Dis Transl Med 2019 Dec 8;5(4):258-266. Epub 2020 Jan 8.

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.

Despite tremendous efforts to fight cancer, it remains a major public health problem and a leading cause of death worldwide. With increased knowledge of cancer pathways and improved technological platforms, precision therapeutics that specifically target aberrant cancer pathways have improved patient outcomes. Nevertheless, a primary cause of unsuccessful cancer therapy remains cancer drug resistance. In this review, we summarize the broad classes of resistance to cancer therapy, particularly pharmacokinetics, the tumor microenvironment, and drug resistance mechanisms. Furthermore, we describe how bacterial-mediated cancer therapy, a bygone mode of treatment, has been revitalized by synthetic biology and is uniquely suited to address the primary resistance mechanisms that confound traditional therapies. Through genetic engineering, we discuss how bacteria can be potent anticancer agents given their tumor targeting potential, anti-tumor activity, safety, and coordinated delivery of anti-cancer drugs.
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http://dx.doi.org/10.1016/j.cdtm.2019.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004931PMC
December 2019

AXL Targeting Abrogates Autophagic Flux and Induces Immunogenic Cell Death in Drug-Resistant Cancer Cells.

J Thorac Oncol 2020 06 1;15(6):973-999. Epub 2020 Feb 1.

Centre for Cancer Biomarkers CCBIO, University of Bergen, Bergen, Norway; Department of Biomedicine, University of Bergen, Bergen, Norway; INSERM UMR 1186, Gustave Roussy, Université Paris-Saclay, Villejuif, France. Electronic address:

Introduction: Acquired cancer therapy resistance evolves under selection pressure of immune surveillance and favors mechanisms that promote drug resistance through cell survival and immune evasion. AXL receptor tyrosine kinase is a mediator of cancer cell phenotypic plasticity and suppression of tumor immunity, and AXL expression is associated with drug resistance and diminished long-term survival in a wide range of malignancies, including NSCLC.

Methods: We aimed to investigate the mechanisms underlying AXL-mediated acquired resistance to first- and third-generation small molecule EGFR tyrosine kinase inhibitors (EGFRi) in NSCLC.

Results: We found that EGFRi resistance was mediated by up-regulation of AXL, and targeting AXL reduced reactivation of the MAPK pathway and blocked onset of acquired resistance to long-term EGFRi treatment in vivo. AXL-expressing EGFRi-resistant cells revealed phenotypic and cell signaling heterogeneity incompatible with a simple bypass signaling mechanism, and were characterized by an increased autophagic flux. AXL kinase inhibition by the small molecule inhibitor bemcentinib or siRNA mediated AXL gene silencing was reported to inhibit the autophagic flux in vitro, bemcentinib treatment blocked clonogenicity and induced immunogenic cell death in drug-resistant NSCLC in vitro, and abrogated the transcription of autophagy-associated genes in vivo. Furthermore, we found a positive correlation between AXL expression and autophagy-associated gene signatures in a large cohort of human NSCLC (n = 1018).

Conclusion: Our results indicate that AXL signaling supports a drug-resistant persister cell phenotype through a novel autophagy-dependent mechanism and reveals a unique immunogenic effect of AXL inhibition on drug-resistant NSCLC cells.
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http://dx.doi.org/10.1016/j.jtho.2020.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397559PMC
June 2020

Betacellulin drives therapy resistance in glioblastoma.

Neuro Oncol 2020 04;22(4):457-469

Department of Neurology, University of California San Francisco (UCSF), San Francisco, California.

Background: The transcription factor signal transducer and activator of transcription 3 (STAT3) drives progression in glioblastoma (GBM), suggesting STAT3 as a therapeutic target. Surprisingly however, GBM cells generally show primary resistance to STAT3 blockade.

Methods: Human glioblastoma cell lines LN229, U87, SF767, and U373, and patient-derived xenografts (PDXs) GBM8 and GBM43 were used to evaluate epidermal growth factor receptor (EGFR) activation during STAT3 inhibition. Protein and gene expression experiments, protein stability assays, cytokine arrays, phospho-tyrosine arrays and EGFR-ligand protein arrays were performed on STAT3 inhibitor-treated cells. To evaluate antitumor activity, we administered a betacellulin (BTC)-neutralizing antibody alone and in combination with STAT3 inhibition. BTC is an EGFR ligand. We therefore treated mice with orthotopic xenografts using the third-generation EGFR inhibitor osimertinib, with or without STAT3 knockdown.

Results: We demonstrate that both small-molecule inhibitors and knockdown of STAT3 led to expression and secretion of the EGFR ligand BTC, resulting in activation of EGFR and subsequent downstream phosphorylation of nuclear factor-kappaB (NF-κB). Neutralizing antibody against BTC abrogated activation of both EGFR and NF-κB in response to inhibition of STAT3; with combinatorial blockade of STAT3 and BTC inducing apoptosis in GBM cells. Blocking EGFR and STAT3 together inhibited tumor growth, improving survival in mice bearing orthotopic GBM PDXs in vivo.

Conclusion: These data reveal a feedback loop among STAT3, EGFR, and NF-κB that mediates primary resistance to STAT3 blockade and suggest strategies for therapeutic intervention.
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http://dx.doi.org/10.1093/neuonc/noz206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158663PMC
April 2020

Co-occurring Alterations in the RAS-MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer.

Clin Cancer Res 2020 01 23;26(2):439-449. Epub 2019 Sep 23.

Department of Medicine, University of California, San Francisco, California.

Purpose: Although patients with advanced-stage non-small cell lung cancers (NSCLC) harboring exon 14 skipping mutations (ex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.

Experimental Design: Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stage ex14-mutated NSCLC.

Results: Prominent co-occurring RAS-MAPK pathway gene alterations (e.g., in ) were detected in NSCLCs with ex14 skipping alterations as compared with -mutated NSCLCs. There was an association between decreased MET TKI treatment response and RAS-MAPK pathway co-occurring alterations. In a preclinical model expressing a canonical ex14 mutation, KRAS overexpression or NF1 downregulation hyperactivated MAPK signaling to promote MET TKI resistance. This resistance was overcome by cotreatment with crizotinib and the MEK inhibitor trametinib.

Conclusions: Our study provides a genomic landscape of co-occurring alterations in advanced-stage ex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980768PMC
January 2020

Synthetic Essentiality of Metabolic Regulator PDHK1 in PTEN-Deficient Cells and Cancers.

Cell Rep 2019 08;28(9):2317-2330.e8

Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; QB3, California Institute for Quantitative Biosciences, San Francisco, CA 94158, USA. Electronic address:

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor and bi-functional lipid and protein phosphatase. We report that the metabolic regulator pyruvate dehydrogenase kinase1 (PDHK1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The PTEN protein phosphatase dephosphorylates nuclear factor κB (NF-κB)-activating protein (NKAP) and limits NFκB activation to suppress expression of PDHK1, a NF-κB target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to induce aerobic glycolysis and PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, a biomarker of decreased patient survival. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers.
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http://dx.doi.org/10.1016/j.celrep.2019.07.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728083PMC
August 2019

Targeting Oncogenic BRAF: Past, Present, and Future.

Cancers (Basel) 2019 Aug 16;11(8). Epub 2019 Aug 16.

Department of Medicine, University of California, San Francisco, CA 94143, USA.

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a "precision medicine" paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies.
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http://dx.doi.org/10.3390/cancers11081197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721448PMC
August 2019

CIC-DUX4 oncoprotein drives sarcoma metastasis and tumorigenesis via distinct regulatory programs.

J Clin Invest 2019 07 22;129(8):3401-3406. Epub 2019 Jul 22.

Department of Medicine.

Transcription factor fusion genes create oncoproteins that drive oncogenesis and represent challenging therapeutic targets. Understanding the molecular targets by which such fusion oncoproteins promote malignancy offers an approach to develop rational treatment strategies to improve clinical outcomes. Capicua-double homeobox 4 (CIC-DUX4) is a transcription factor fusion oncoprotein that defines certain undifferentiated round cell sarcomas with high metastatic propensity and poor clinical outcomes. The molecular targets regulated by the CIC-DUX4 oncoprotein that promote this aggressive malignancy remain largely unknown. We demonstrated that increased expression of ETS variant 4 (ETV4) and cyclin E1 (CCNE1) occurs via neomorphic, direct effects of CIC-DUX4 and drives tumor metastasis and survival, respectively. We uncovered a molecular dependence on the CCNE-CDK2 cell cycle complex that renders CIC-DUX4-expressing tumors sensitive to inhibition of the CCNE-CDK2 complex, suggesting a therapeutic strategy for CIC-DUX4-expressing tumors. Our findings highlight a paradigm of functional diversification of transcriptional repertoires controlled by a genetically aberrant transcriptional regulator, with therapeutic implications.
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http://dx.doi.org/10.1172/JCI126366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668665PMC
July 2019
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