Publications by authors named "Maurizio Scaltriti"

115 Publications

José Baselga (1959-2021).

Cancer Cell 2021 May 29;39(5):581-582. Epub 2021 Apr 29.

Translational Medicine, Oncology R&D, AstraZeneca, Boston, MA, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ccell.2021.04.003DOI Listing
May 2021

José Manuel Baselga (1959-2021).

Science 2021 Apr;372(6540):350

AstraZeneca, Cambridge, UK.

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http://dx.doi.org/10.1126/science.abi7805DOI Listing
April 2021

How a new drug is born.

Eur Heart J 2021 Mar 15. Epub 2021 Mar 15.

Early Oncology, AstraZeneca, 35 Gatehouse Park, Waltham, MA 02451, USA.

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http://dx.doi.org/10.1093/eurheartj/ehab076DOI Listing
March 2021

Genomic alterations in PIK3CA-mutated breast cancer result in mTORC1 activation and limit sensitivity to PI3Kα inhibitors.

Cancer Res 2021 Mar 8. Epub 2021 Mar 8.

Department of Pathology, Memorial Sloan Kettering Cancer Center

PI3Kα inhibitors have shown clinical activity in PIK3CA-mutated estrogen receptor-positive (ER+) breast cancer patients. Using whole genome CRISPR/Cas9 sgRNA knockout screens, we identified and validated several negative regulators of mTORC1 whose loss confers resistance to PI3Kα inhibition. Among the top candidates were TSC1, TSC2, TBC1D7, AKT1S1, STK11, MARK2, PDE7A, DEPDC5, NPRL2, NPRL3, C12orf66, SZT2 and ITFG2. Loss of these genes invariably results in sustained mTOR signaling under pharmacological inhibition of the PI3K-AKT pathway. Moreover, resistance could be prevented or overcome by mTOR inhibition, confirming the causative role of sustained mTOR activity in limiting the sensitivity to PI3Kα inhibition. Cumulatively, genomic alterations affecting these genes are identified in about 15% of PIK3CA-mutated breast tumors and appear to be mutually exclusive. This study improves our understanding of the role of mTOR signaling restoration in leading to resistance to PI3Kα inhibition and proposes therapeutic strategies to prevent or revert this resistance.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3232DOI Listing
March 2021

Molecular mechanisms of assembly and TRIP13-mediated remodeling of the human Shieldin complex.

Proc Natl Acad Sci U S A 2021 Feb;118(8)

Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065;

The Shieldin complex, composed of REV7, SHLD1, SHLD2, and SHLD3, protects DNA double-strand breaks (DSBs) to promote nonhomologous end joining. The AAA ATPase TRIP13 remodels Shieldin to regulate DNA repair pathway choice. Here we report crystal structures of human SHLD3-REV7 binary and fused SHLD2-SHLD3-REV7 ternary complexes, revealing that assembly of Shieldin requires fused SHLD2-SHLD3 induced conformational heterodimerization of open (O-REV7) and closed (C-REV7) forms of REV7. We also report the cryogenic electron microscopy (cryo-EM) structures of the ATPγS-bound fused SHLD2-SHLD3-REV7-TRIP13 complexes, uncovering the principles underlying the TRIP13-mediated disassembly mechanism of the Shieldin complex. We demonstrate that the N terminus of REV7 inserts into the central channel of TRIP13, setting the stage for pulling the unfolded N-terminal peptide of C-REV7 through the central TRIP13 hexameric channel. The primary interface involves contacts between the safety-belt segment of C-REV7 and a conserved and negatively charged loop of TRIP13. This process is mediated by ATP hydrolysis-triggered rotatory motions of the TRIP13 ATPase, thereby resulting in the disassembly of the Shieldin complex.
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http://dx.doi.org/10.1073/pnas.2024512118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923543PMC
February 2021

Targeting transcription of MCL-1 sensitizes HER2-amplified breast cancers to HER2 inhibitors.

Cell Death Dis 2021 Feb 15;12(2):179. Epub 2021 Feb 15.

Department of Oral and Craniofacial Molecular Biology, Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.

Human epidermal growth factor receptor 2 gene (HER2) is focally amplified in approximately 20% of breast cancers. HER2 inhibitors alone are not effective, and sensitizing agents will be necessary to move away from a reliance on heavily toxic chemotherapeutics. We recently demonstrated that the efficacy of HER2 inhibitors is mitigated by uniformly low levels of the myeloid cell leukemia 1 (MCL-1) endogenous inhibitor, NOXA. Emerging clinical data have demonstrated that clinically advanced cyclin-dependent kinase (CDK) inhibitors are effective MCL-1 inhibitors in patients, and, importantly, well tolerated. We, therefore, tested whether the CDK inhibitor, dinaciclib, could block MCL-1 in preclinical HER2-amplified breast cancer models and therefore sensitize these cancers to dual HER2/EGFR inhibitors neratinib and lapatinib, as well as to the novel selective HER2 inhibitor tucatinib. Indeed, we found dinaciclib suppresses MCL-1 RNA and is highly effective at sensitizing HER2 inhibitors both in vitro and in vivo. This combination was tolerable in vivo. Mechanistically, liberating the effector BCL-2 protein, BAK, from MCL-1 results in robust apoptosis. Thus, clinically advanced CDK inhibitors may effectively combine with HER2 inhibitors and present a chemotherapy-free therapeutic strategy in HER2-amplified breast cancer, which can be tested immediately in the clinic.
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http://dx.doi.org/10.1038/s41419-021-03457-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884408PMC
February 2021

Canakinumab as treatment for COVID-19-related pneumonia: A prospective case-control study.

Int J Infect Dis 2021 Mar 29;104:433-440. Epub 2020 Dec 29.

COVID Unit, Azienda Socio Sanitaria Territoriale di Cremona, Cremona, Italy.

Objectives: Canakinumab is an IL-1β antibody that neutralises the activity of IL-1β. This study examined the efficacy and safety of canakinumab in patients with moderate COVID-19-related pneumonia.

Design: This study aimed to evaluate the reduction in duration of hospitalisation with adequate oxygen status. Forty-eight patients with moderate COVID-19-related pneumonia were asked to participate in the prospective case-control study: 33 patients (cases) signed informed consent and received canakinumab (Cohort 1) and 15 patients (Controls) refused to receive the experimental drug and received institutional standard of care (Cohort 2).

Results: Hospital discharge within 21 days was seen in 63% of patients in Cohort 1 vs. 0% in Cohort 2 (median 14 vs. 26 days, respectively; p < 0.001). There was significant clinical improvement in ventilation regimes following administration of canakinumab compared with Cohort 2 (Stuart-Maxwell test for paired data, p < 0.001). Patients treated with canakinumab experienced a significant increase in PaO:FiO (p < 0.001) and reduction in lung damage by CT (p = 0.01), along with significant decreases in immune/inflammation markers that were not observed in Cohort 2. Only mild side-effects were seen in patients treated with canakinumab; survival at 60 days was 90.0% (95% CI 71.9-96.7) in patients treated with canakinumab and 73.3% (95% CI 43.6-89.1) for Cohort 2.

Conclusions: Treatment with canakinumab in patients with COVID-19-related pneumonia rapidly restored normal oxygen status, decreased the need for invasive mechanical ventilation, and was associated with earlier hospital discharge and favourable prognosis versus standard of care.
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http://dx.doi.org/10.1016/j.ijid.2020.12.073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771302PMC
March 2021

Phase I Basket Study of Taselisib, an Isoform-Selective PI3K Inhibitor, in Patients with -Mutant Cancers.

Clin Cancer Res 2021 Jan 4;27(2):447-459. Epub 2020 Nov 4.

Memorial Sloan Kettering Cancer Center, Memorial Hospital, New York, New York.

Purpose: Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (), which encodes the p110α catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with -mutant cancers with the isoform-specific PI3K inhibitor taselisib.

Patients And Methods: Patients were enrolled on the basis of local mutation testing into one of 11 histology-specific cohorts and treated with taselisib at 6 or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed.

Results: A total of 166 patients with -mutant cancers were enrolled. The confirmed response rate was 9%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10%), and other cancers, plus in tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront ( and ) and postprogression through reactivation of the PI3K pathway (, and ). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index.

Conclusions: Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target -mutant tumors.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2657DOI Listing
January 2021

CDK 4/6 Inhibition Overcomes Acquired and Inherent Resistance to PI3Kα Inhibition in Pre-Clinical Models of Head and Neck Squamous Cell Carcinoma.

J Clin Med 2020 Oct 7;9(10). Epub 2020 Oct 7.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.

Activating alterations in , the gene coding for the catalytic subunit of phosphoinositide-3-kinase (PI3K), are prevalent in head and neck squamous cell carcinoma (HNSCC) and thought to be one of the main drivers of these tumors. However, early clinical trials on PI3K inhibitors (PI3Ki) have been disappointing due to the limited durability of the activity of these drugs. To investigate the resistance mechanisms to PI3Ki and attempt to overcome them, we conducted a molecular-based study using both HNSCC cell lines and patient-derived xenografts (PDXs). We sought to simulate and dissect the molecular pathways that come into play in PIK3CA-altered HNSCC treated with isoform-specific PI3Ki (BYL719, GDC0032). In vitro assays of cell viability and protein expression indicate that activation of the mTOR and cyclin D1 pathways is associated with resistance to PI3Ki. Specifically, in BYL719-resistant cells, BYL719 treatment did not induce pS6 and pRB inhibition as detected in BYL719-sensitive cells. By combining PI3Ki with either mammalian target of rapamycin complex 1 (mTORC1) or cyclin D1 kinase (CDK) 4/6 specific inhibitors (RAD001 and abemaciclib, respectively), we were able to overcome the acquired resistance. Furthermore, we found that PI3Ki and CDK 4/6 inhibitors have a synergistic anti-tumor effect when combined in human papillomavirus (HPV)-negative/PIK3CA-WT tumors. These findings provide a rationale for combining PI3Ki and CDK 4/6 inhibitors to enhance anti-tumor efficacy in HNSCC patients.
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http://dx.doi.org/10.3390/jcm9103214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601167PMC
October 2020

TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors.

Cancer Discov 2020 Oct 1. Epub 2020 Oct 1.

Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York.

On-target resistance to next-generation TRK inhibitors in TRK fusion-positive cancers is largely uncharacterized. In patients with these tumors, we found that TRK xDFG mutations confer resistance to type I next-generation TRK inhibitors designed to maintain potency against several kinase domain mutations. Computational modeling and biochemical assays showed that TRKA and TRKC xDFG substitutions reduce drug binding by generating steric hindrance. Concurrently, these mutations stabilize the inactive (DFG-out) conformations of the kinases, thus sensitizing these kinases to type II TRK inhibitors. Consistently, type II inhibitors impede the growth and TRK-mediated signaling of xDFG-mutant isogenic and patient-derived models. Collectively, these data demonstrate that adaptive conformational resistance can be abrogated by shifting kinase engagement modes. Given the prior identification of paralogous xDFG resistance mutations in other oncogene-addicted cancers, these findings provide insights into rational type II drug design by leveraging inhibitor class affinity switching to address recalcitrant resistant alterations. SIGNIFICANCE: In TRK fusion-positive cancers, TRK xDFG substitutions represent a shared liability for type I TRK inhibitors. In contrast, they represent a potential biomarker of type II TRK inhibitor activity. As all currently available type II agents are multikinase inhibitors, rational drug design should focus on selective type II inhibitor creation.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012405PMC
October 2020

Metabolic Imaging Detects Resistance to PI3Kα Inhibition Mediated by Persistent FOXM1 Expression in ER Breast Cancer.

Cancer Cell 2020 10 24;38(4):516-533.e9. Epub 2020 Sep 24.

Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge, UK; Cancer Research UK Cambridge Cancer Centre, Cambridge, UK; Department of Biochemistry, University of Cambridge, Cambridge UK. Electronic address:

PIK3CA, encoding the PI3Kα isoform, is the most frequently mutated oncogene in estrogen receptor (ER)-positive breast cancer. Isoform-selective PI3K inhibitors are used clinically but intrinsic and acquired resistance limits their utility. Improved selection of patients that will benefit from these drugs requires predictive biomarkers. We show here that persistent FOXM1 expression following drug treatment is a biomarker of resistance to PI3Kα inhibition in ER breast cancer. FOXM1 drives expression of lactate dehydrogenase (LDH) but not hexokinase 2 (HK-II). The downstream metabolic changes can therefore be detected using MRI of LDH-catalyzed hyperpolarized C label exchange between pyruvate and lactate but not by positron emission tomography measurements of HK-II-mediated trapping of the glucose analog 2-deoxy-2-[F]fluorodeoxyglucose. Rapid assessment of treatment response in breast cancer using this imaging method could help identify patients that benefit from PI3Kα inhibition and design drug combinations to counteract the emergence of resistance.
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http://dx.doi.org/10.1016/j.ccell.2020.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562820PMC
October 2020

Genomic Characterization of -Driven Biliary Cancer and a Case of Response to Ado-Trastuzumab Emtansine.

JCO Precis Oncol 2019 17;3. Epub 2019 Oct 17.

Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Biliary tract cancers (BTCs), which include intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (EHC), and gallbladder cancer (GBC), have limited treatment options. We sought to comprehensively examine the clinical and molecular characteristics of BTCs with amplification or mutation of .

Methods: Demographic, outcome, and treatment response data were collected for patients with -altered BTC identified by next-generation sequencing with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets from 2014 to 2018.

Results: A total of 517 patients with BTC underwent next-generation sequencing (ICC, n = 313; EHC, n = 93; GBC, n = 111). Twenty-eight patients (5.4%) had alterations, including 2.7% with gene amplification, 2.3% with mutation, and 0.4% with concurrent amplification and mutation. The prevalence of gene alterations was significantly higher in GBC (12.6%) than in ICC (2.2%) and EHC (7.5%; < .001). In amplified tumors, the median fold change was 6.4 (range, 2.1 to 19.7), while in -mutant tumors, the most frequent mutated domain was the extracellular domain (32%), with all mutations in this region involving the S310 codon. Frequent co-altered genes in this cohort were (54%), (21%), and (18%); amplification/mutation was found in 7% of patients. One patient with -amplified EHC who enrolled in a basket trial (ClinicalTrials.gov identifier: NCT02675829) had a partial response to the human epidermal growth factor receptor 2-targeted antibody-drug conjugate ado-trastuzumab emtansine.

Conclusion: alterations are present in 5.4% of BTCs. When present, the degree of gene amplification is often high, and S310 codon mutations are the most common hotspot. These features, along with the presented case, support further development of human epidermal growth factor receptor 2-targeted therapy in -mutant and/or -amplified BTC.
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http://dx.doi.org/10.1200/PO.19.00223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446346PMC
October 2019

Personalized cancer therapy prioritization based on driver alteration co-occurrence patterns.

Genome Med 2020 09 9;12(1):78. Epub 2020 Sep 9.

Joint IRB-BSC-CRG Program in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Catalonia, Spain.

Identification of actionable genomic vulnerabilities is key to precision oncology. Utilizing a large-scale drug screening in patient-derived xenografts, we uncover driver gene alteration connections, derive driver co-occurrence (DCO) networks, and relate these to drug sensitivity. Our collection of 53 drug-response predictors attains an average balanced accuracy of 58% in a cross-validation setting, rising to 66% for a subset of high-confidence predictions. We experimentally validated 12 out of 14 predictions in mice and adapted our strategy to obtain drug-response models from patients' progression-free survival data. Our strategy reveals links between oncogenic alterations, increasing the clinical impact of genomic profiling.
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http://dx.doi.org/10.1186/s13073-020-00774-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488324PMC
September 2020

FOXA1 Mutations Reveal Distinct Chromatin Profiles and Influence Therapeutic Response in Breast Cancer.

Cancer Cell 2020 10 3;38(4):534-550.e9. Epub 2020 Sep 3.

Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Mutations in the pioneer transcription factor FOXA1 are a hallmark of estrogen receptor-positive (ER) breast cancers. Examining FOXA1 in ∼5,000 breast cancer patients identifies several hotspot mutations in the Wing2 region and a breast cancer-specific mutation SY242CS, located in the third β strand. Using a clinico-genomically curated cohort, together with breast cancer models, we find that FOXA1 mutations associate with a lower response to aromatase inhibitors. Mechanistically, Wing2 mutations display increased chromatin binding at ER loci upon estrogen stimulation, and an enhanced ER-mediated transcription without changes in chromatin accessibility. In contrast, SY242CS shows neomorphic properties that include the ability to open distinct chromatin regions and activate an alternative cistrome and transcriptome. Structural modeling predicts that SY242CS confers a conformational change that mediates stable binding to a non-canonical DNA motif. Taken together, our results provide insights into how FOXA1 mutations perturb its function to dictate cancer progression and therapeutic response.
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http://dx.doi.org/10.1016/j.ccell.2020.08.003DOI Listing
October 2020

Alterations in and promote clinical resistance to alpelisib plus aromatase inhibitors.

Nat Cancer 2020 Apr 23;1(4):382-393. Epub 2020 Mar 23.

Human Oncology and Pathogenesis Program, MSKCC, New York, NY.

Alpelisib is a selective inhibitor of PI3Kα, shown to improve outcomes for mutant, hormone receptor positive (HR+) metastatic breast cancers (MBC) when combined with antiestrogen therapy. To uncover mechanisms of resistance, we conducted a detailed, longitudinal analysis of tumor and plasma circulating tumor DNA among such patients from a phase I/II trial combining alpelisib with an aromatase inhibitor (AI) (NCT01870505). The trial's primary objective was to establish safety with maculopapular rash emerging as the most common grade 3 adverse event (33%). Among 44 evaluable patients, the observed clinical benefit rate was 52%. Correlating genetic alterations with outcome, we identified loss-of-function mutations in 25% of patients with resistance. activating mutations also expanded in number and allele fraction during treatment and were associated with resistance. These data indicate that genomic alterations that mediate resistance to alpelisib or antiestrogen may promote disease progression and highlight loss as a recurrent mechanism of resistance to PI3Kα inhibition.
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http://dx.doi.org/10.1038/s43018-020-0047-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450824PMC
April 2020

Phase and context shape the function of composite oncogenic mutations.

Nature 2020 06 27;582(7810):100-103. Epub 2020 May 27.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Cancers develop as a result of driver mutations that lead to clonal outgrowth and the evolution of disease. The discovery and functional characterization of individual driver mutations are central aims of cancer research, and have elucidated myriad phenotypes and therapeutic vulnerabilities. However, the serial genetic evolution of mutant cancer genes and the allelic context in which they arise is poorly understood in both common and rare cancer genes and tumour types. Here we find that nearly one in four human tumours contains a composite mutation of a cancer-associated gene, defined as two or more nonsynonymous somatic mutations in the same gene and tumour. Composite mutations are enriched in specific genes, have an elevated rate of use of less-common hotspot mutations acquired in a chronology driven in part by oncogenic fitness, and arise in an allelic configuration that reflects context-specific selective pressures. cis-acting composite mutations are hypermorphic in some genes in which dosage effects predominate (such as TERT), whereas they lead to selection of function in other genes (such as TP53). Collectively, composite mutations are driver alterations that arise from context- and allele-specific selective pressures that are dependent in part on gene and mutation function, and which lead to complex-often neomorphic-functions of biological and therapeutic importance.
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http://dx.doi.org/10.1038/s41586-020-2315-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294994PMC
June 2020

Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts.

Nat Commun 2020 04 24;11(1):1975. Epub 2020 Apr 24.

Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.
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http://dx.doi.org/10.1038/s41467-020-15885-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181640PMC
April 2020

Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with -Mutant, ER-Positive Metastatic Breast Cancer.

Clin Cancer Res 2020 08 20;26(15):3947-3957. Epub 2020 Apr 20.

Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: The activating mutation occurs in approximately 7% of estrogen receptor-positive (ER) metastatic breast cancer (MBC). We report, from a multipart, first-in-human, phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of patients with -mutant ER MBC.

Patients And Methods: Patients with an mutation, detected by local (next-generation sequencing) or central (plasma-based BEAMing) testing, received capivasertib 480 mg twice daily, 4 days on, 3 days off, weekly or 400 mg twice daily combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS), and clinical benefit rate at 24 weeks (CBR). Biomarker analyses were conducted in the combination cohort.

Results: From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although the latter group may have had more aggressive disease at baseline. mutations were detectable in plasma by BEAMing (95%, 41/43), droplet digital PCR (80%, 33/41), and next-generation sequencing (76%, 31/41). A ≥50% decrease in at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy [most frequent grade ≥3 adverse events: rash (9% vs. 20%), hyperglycemia (5% vs. 30%), diarrhea (5% vs. 10%)].

Conclusions: Capivasertib demonstrated clinically meaningful activity in heavily pretreated patients with -mutant ER MBC, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415507PMC
August 2020

Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts.

Clin Cancer Res 2020 07 27;26(14):3720-3731. Epub 2020 Mar 27.

Department of Medical Oncology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Purpose: AZD5363/capivasertib is a pan-AKT catalytic inhibitor with promising activity in combination with paclitaxel in triple-negative metastatic breast cancer harboring PI3K/AKT-pathway alterations and in estrogen receptor-positive breast cancer in combination with fulvestrant. Here, we aimed to identify response biomarkers and uncover mechanisms of resistance to AZD5363 and its combination with paclitaxel.

Experimental Design: Genetic and proteomic markers were analyzed in 28 HER2-negative patient-derived xenografts (PDXs) and in patient samples, and correlated to AZD5363 sensitivity as single agent and in combination with paclitaxel.

Results: Four PDX were derived from patients receiving AZD5363 in the clinic which exhibited concordant treatment response. Mutations in / and absence of mTOR complex 1 (mTORC1)-activating alterations, for example, in or , were associated with sensitivity to AZD5363 monotherapy. Interestingly, excluding from the composite biomarker increased its accuracy from 64% to 89%. Moreover, resistant PDXs exhibited low baseline pAKT S473 and residual pS6 S235 upon treatment, suggesting that parallel pathways bypass AKT/S6K1 signaling in these models. We identified two mechanisms of acquired resistance to AZD5363: cyclin D1 overexpression and loss of p.E17K.

Conclusions: This study provides insight into putative predictive biomarkers of response and acquired resistance to AZD5363 in HER2-negative metastatic breast cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814659PMC
July 2020

HER2-Mediated Internalization of Cytotoxic Agents in Amplified or Mutant Lung Cancers.

Cancer Discov 2020 May 25;10(5):674-687. Epub 2020 Mar 25.

mProbe Inc., Rockville, Maryland.

Amplification of and oncogenic mutations in , the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody-drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with -amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy. SIGNIFICANCE: T-DM1 is clinically effective in lung cancers with amplification of or mutations in . This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy...
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http://dx.doi.org/10.1158/2159-8290.CD-20-0215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196485PMC
May 2020

In Vitro Establishment of a Genetically Engineered Murine Head and Neck Cancer Cell Line using an Adeno-Associated Virus-Cas9 System.

J Vis Exp 2020 01 9(155). Epub 2020 Jan 9.

The Shraga Segal Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev; Faculty of Health Sciences, Ben-Gurion University of the Negev;

The use of primary normal epithelial cells makes it possible to reproducibly induce genomic alterations required for cellular transformation by introducing specific mutations in oncogenes and tumor suppressor genes, using clustered regulatory interspaced short palindromic repeat (CRISPR)-based genome editing technology in mice. This technology allows us to accurately mimic the genetic changes that occur in human cancers using mice. By genetically transforming murine primary cells, we can better study cancer development, progression, treatment, and diagnosis. In this study, we used Cre-inducible Cas9 mouse tongue epithelial cells to enable genome editing using adeno-associated virus (AAV) in vitro. Specifically, by altering KRAS, p53, and APC in normal tongue epithelial cells, we generated a murine head and neck cancer (HNC) cell line in vitro,which is tumorigenic in syngeneic mice. The method presented here describes in detail how to generate HNC cell lines with specific genomic alterations and explains their suitability for predicting tumor progression in syngeneic mice. We envision that this promising method will be informative and useful to study tumor biology and therapy of HNC.
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http://dx.doi.org/10.3791/60410DOI Listing
January 2020

ARID1A determines luminal identity and therapeutic response in estrogen-receptor-positive breast cancer.

Nat Genet 2020 02 13;52(2):198-207. Epub 2020 Jan 13.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Mutations in ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, are the most common alterations of the SWI/SNF complex in estrogen-receptor-positive (ER) breast cancer. We identify that ARID1A inactivating mutations are present at a high frequency in advanced endocrine-resistant ER breast cancer. An epigenome CRISPR-CAS9 knockout (KO) screen identifies ARID1A as the top candidate whose loss determines resistance to the ER degrader fulvestrant. ARID1A inactivation in cells and in patients leads to resistance to ER degraders by facilitating a switch from ER-dependent luminal cells to ER-independent basal-like cells. Cellular plasticity is mediated by loss of ARID1A-dependent SWI/SNF complex targeting to genomic sites of the luminal lineage-determining transcription factors including ER, forkhead box protein A1 (FOXA1) and GATA-binding factor 3 (GATA3). ARID1A also regulates genome-wide ER-FOXA1 chromatin interactions and ER-dependent transcription. Altogether, we uncover a critical role for ARID1A in maintaining luminal cell identity and endocrine therapeutic response in ER breast cancer.
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http://dx.doi.org/10.1038/s41588-019-0554-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341683PMC
February 2020

TRK Fusions Are Enriched in Cancers with Uncommon Histologies and the Absence of Canonical Driver Mutations.

Clin Cancer Res 2020 04 23;26(7):1624-1632. Epub 2019 Dec 23.

Department of Medicine, Memorial Sloan Kettering, New York, New York.

Purpose: TRK inhibitors achieve marked tumor-agnostic efficacy in TRK fusion-positive cancers and consequently are now an established standard of care. Little is known, however, about the demographics, outcomes, response to alternative standard therapies, or genomic characteristics of TRK fusion-positive cancers.

Experimental Design: Utilizing a center-wide screening program involving more than 26,000 prospectively sequenced patients, genomic and clinical data from all cases with TRK fusions were extracted. An integrated analysis was performed of genomic, therapeutic, and phenomic outcomes.

Results: We identified 76 cases with confirmed TRK fusions (0.28% overall prevalence) involving 48 unique rearrangements and 17 cancer types. The presence of a TRK fusion was associated with depletion of concurrent oncogenic drivers ( < 0.001) and lower tumor mutation burden ( < 0.001), with the exception of colorectal cancer where TRK fusions cooccur with microsatellite instability (MSI-H). Longitudinal profiling in a subset of patients indicated that TRK fusions were present in all sampled timepoints in 82% (14/17) of cases. Progression-free survival on first-line therapy, excluding TRK inhibitors, administered for advanced disease was 9.6 months [95% confidence interval (CI), 4.8-13.2]. The best overall response rate achieved with chemotherapy containing-regimens across all lines of therapy was 63% (95% CI, 41-81). Among 12 patients treated with checkpoint inhibitors, a patient with MSI-H colorectal cancer had the only observed response.

Conclusions: TRK fusion-positive cancers can respond to alternative standards of care, although efficacy of immunotherapy in the absence of other predictive biomarkers (MSI-H) appears limited. TRK fusions are present in tumors with simple genomes lacking in concurrent drivers that may partially explain the tumor-agnostic efficacy of TRK inhibitors.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7124988PMC
April 2020

Efficacy and Determinants of Response to HER Kinase Inhibition in -Mutant Metastatic Breast Cancer.

Cancer Discov 2020 02 5;10(2):198-213. Epub 2019 Dec 5.

Memorial Sloan Kettering Cancer Center, New York, New York.

mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with -mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating or alterations were associated with poor treatment outcome. Similarly, acquisition of multiple -activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both and acquired resistance to neratinib. SIGNIFICANCE: mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer..
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http://dx.doi.org/10.1158/2159-8290.CD-19-0966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007377PMC
February 2020

Double mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors.

Science 2019 11;366(6466):714-723

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Activating mutations in are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3Kα) inhibitors have been approved for therapy. To characterize determinants of sensitivity to these agents, we analyzed -mutant cancer genomes and observed the presence of multiple mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double mutations are in cis on the same allele and result in increased PI3K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased p110α membrane lipid binding. Double mutations predict increased sensitivity to PI3Kα inhibitors compared with single-hotspot mutations.
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http://dx.doi.org/10.1126/science.aaw9032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173400PMC
November 2019

Resistance to TRK inhibition mediated by convergent MAPK pathway activation.

Nat Med 2019 09 12;25(9):1422-1427. Epub 2019 Aug 12.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition. With the recent approval of the first selective TRK inhibitor, larotrectinib, for patients with any TRK-fusion-positive adult or pediatric solid tumor, to identify mechanisms of treatment failure after initial response has become of immediate therapeutic relevance. So far, the only known resistance mechanism is the acquisition of on-target TRK kinase domain mutations, which interfere with drug binding and can potentially be addressable through second-generation TRK inhibitors. Here, we report off-target resistance in patients treated with TRK inhibitors and in patient-derived models, mediated by genomic alterations that converge to activate the mitogen-activated protein kinase (MAPK) pathway. MAPK pathway-directed targeted therapy, administered alone or in combination with TRK inhibition, re-established disease control. Experimental modeling further suggests that upfront dual inhibition of TRK and MEK may delay time to progression in cancer types prone to the genomic acquisition of MAPK pathway-activating alterations. Collectively, these data suggest that a subset of patients will develop off-target mechanisms of resistance to TRK inhibition with potential implications for clinical management and future clinical trial design.
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http://dx.doi.org/10.1038/s41591-019-0542-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736691PMC
September 2019

Cell-free DNA analysis in healthy individuals by next-generation sequencing: a proof of concept and technical validation study.

Cell Death Dis 2019 07 11;10(7):534. Epub 2019 Jul 11.

Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.

Pre-symptomatic screening of genetic alterations might help identify subpopulations of individuals that could enter into early access prevention programs. Since liquid biopsy is minimally invasive it can be used for longitudinal studies in healthy volunteers to monitor events of progression from normal tissue to pre-cancerous and cancerous condition. Yet, cell-free DNA (cfDNA) analysis in healthy individuals comes with substantial challenges such as the lack of large cohort studies addressing the impact of mutations in healthy individuals or the low abundance of cfDNA in plasma. In this study, we aimed to investigate the technical feasibility of cfDNA analysis in a collection of 114 clinically healthy individuals. We first addressed the impact of pre-analytical factors such as cfDNA yield and quality on sequencing performance and compared healthy to cancer donor samples. We then confirmed the validity of our testing strategy by evaluating the mutational status concordance in matched tissue and plasma specimens collected from cancer patients. Finally, we screened our group of healthy donors for genetic alterations, comparing individuals who did not develop any tumor to patients who developed either a benign neoplasm or cancer during 1-10 years of follow-up time. To conclude, we have established a rapid and reliable liquid biopsy workflow that allowed us to study genomic alterations with a limit of detection as low as 0.08% of variant allelic frequency in healthy individuals. We detected pathogenic cancer mutations in four healthy donors that later developed a benign neoplasm or invasive breast cancer up to 10 years after blood collection. Even though larger prospective studies are needed to address the specificity and sensitivity of liquid biopsy as a clinical tool for early cancer detection, systematic screening of healthy individuals will help understanding early events of tumor formation.
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http://dx.doi.org/10.1038/s41419-019-1770-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624284PMC
July 2019

Solid pseudopapillary neoplasms of the pancreas are dependent on the Wnt pathway.

Mol Oncol 2019 08 3;13(8):1684-1692. Epub 2019 Jul 3.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Solid pseudopapillary neoplasms (SPNs) are rare and relatively indolent tumors of the pancreas. While primary SPNs can be surgically resected, there are currently no therapies available for patients with advanced stage disease. Given that these tumors frequently carry CTNNB1 hotspot (recurrently mutated loci in a gene) mutations resulting in β-catenin nuclear accumulation, it has been speculated that the Wnt pathway may be a driver in this disease. Here, we present a comprehensive "multi-omics" study where the genome, transcriptome, and methylome of SPNs were analyzed. We found that SPNs are characterized by a low-complexity genome where somatic mutations in CTNNB1, present in 100% of the cases, are the only actionable genomic lesions. Compared to more common subtypes of pancreatic tumors (adenocarcinomas and pancreatic neuroendocrine tumors), SPNs show high expression levels of genes belonging to the Wnt pathway. Their methylome was consistent with an epithelial cell origin and a general upregulation of Wnt pathway genes. Clinical studies to evaluate the exquisite sensitivity of SPNs to inhibitors of the Wnt pathway are warranted.
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http://dx.doi.org/10.1002/1878-0261.12490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6670010PMC
August 2019

Prevalence and role of HER2 mutations in cancer.

Pharmacol Ther 2019 07 2;199:188-196. Epub 2019 Apr 2.

Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

HER2 activating mutations act as oncogenic drivers in various cancer types. In the clinic, they can be identified by next generation sequencing (NGS) in either tumor biopsies or circulating cell-free DNA (cfDNA). Preclinical data indicate that HER2 "hot spot" mutations are constitutively active, have transforming capacity in vitro and in vivo and show variable sensitivity to anti-HER2 based therapies. Recent clinical trials also revealed activity of HER2-targeted drugs against a variety of tumors harboring HER2 mutations. Here, we review the prevalence and type of HER2 mutations identified in different human cancers, their biochemical and biological characterization, and their sensitivity to anti HER2-based therapies in both preclinical and clinical settings.
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http://dx.doi.org/10.1016/j.pharmthera.2019.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571037PMC
July 2019

PI3K Inhibition Activates SGK1 via a Feedback Loop to Promote Chromatin-Based Regulation of ER-Dependent Gene Expression.

Cell Rep 2019 04;27(1):294-306.e5

Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Research & Development Oncology, AstraZeneca Pharmaceuticals, Gaithersburg, MD 20878, USA. Electronic address:

The PI3K pathway integrates extracellular stimuli to phosphorylate effectors such as AKT and serum-and-glucocorticoid-regulated kinase (SGK1). We have previously reported that the PI3K pathway regulates estrogen receptor (ER)-dependent transcription in breast cancer through the phosphorylation of the lysine methyltransferase KMT2D by AKT. Here, we show that PI3Kα inhibition, via a negative-feedback loop, activates SGK1 to promote chromatin-based regulation of ER-dependent transcription. PI3K/AKT inhibitors activate ER, which promotes SGK1 transcription through direct binding to its promoter. Elevated SGK1, in turn, phosphorylates KMT2D, suppressing its function, leading to a loss of methylation of lysine 4 on histone H3 (H3K4) and a repressive chromatin state at ER loci to attenuate ER activity. Thus, SGK1 regulates the chromatin landscape and ER-dependent transcription via the direct phosphorylation of KMT2D. These findings reveal an ER-SGK1-KMT2D signaling circuit aimed to attenuate ER response through a role for SGK1 to program chromatin and ER transcriptional output.
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http://dx.doi.org/10.1016/j.celrep.2019.02.111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503687PMC
April 2019