Publications by authors named "William G Kaelin"

144 Publications

Targeting oncoproteins with a positive selection assay for protein degraders.

Sci Adv 2021 Feb 5;7(6). Epub 2021 Feb 5.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Most intracellular proteins lack hydrophobic pockets suitable for altering their function with drug-like small molecules. Recent studies indicate that some undruggable proteins can be targeted by compounds that can degrade them. For example, thalidomide-like drugs (IMiDs) degrade the critical multiple myeloma transcription factors IKZF1 and IKZF3 by recruiting them to the cereblon E3 ubiquitin ligase. Current loss of signal ("down") assays for identifying degraders often exhibit poor signal-to-noise ratios, narrow dynamic ranges, and false positives from compounds that nonspecifically suppress transcription or translation. Here, we describe a gain of signal ("up") assay for degraders. In arrayed chemical screens, we identified novel IMiD-like IKZF1 degraders and Spautin-1, which, unlike the IMiDs, degrades IKZF1 in a cereblon-independent manner. In a pooled CRISPR-Cas9-based screen, we found that CDK2 regulates the abundance of the ASCL1 oncogenic transcription factor. This methodology should facilitate the identification of drugs that directly or indirectly degrade undruggable proteins.
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http://dx.doi.org/10.1126/sciadv.abd6263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864573PMC
February 2021

2-Oxoglutarate-dependent dioxygenases in cancer.

Nat Rev Cancer 2020 12 21;20(12):710-726. Epub 2020 Oct 21.

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA.

2-Oxoglutarate-dependent dioxygenases (2OGDDs) are a superfamily of enzymes that play diverse roles in many biological processes, including regulation of hypoxia-inducible factor-mediated adaptation to hypoxia, extracellular matrix formation, epigenetic regulation of gene transcription and the reprogramming of cellular metabolism. 2OGDDs all require oxygen, reduced iron and 2-oxoglutarate (also known as α-ketoglutarate) to function, although their affinities for each of these co-substrates, and hence their sensitivity to depletion of specific co-substrates, varies widely. Numerous 2OGDDs are recurrently dysregulated in cancer. Moreover, cancer-specific metabolic changes, such as those that occur subsequent to mutations in the genes encoding succinate dehydrogenase, fumarate hydratase or isocitrate dehydrogenase, can dysregulate specific 2OGDDs. This latter observation suggests that the role of 2OGDDs in cancer extends beyond cancers that harbour mutations in the genes encoding members of the 2OGDD superfamily. Herein, we review the regulation of 2OGDDs in normal cells and how that regulation is corrupted in cancer.
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http://dx.doi.org/10.1038/s41568-020-00303-3DOI Listing
December 2020

Targeting the HIF2-VEGF axis in renal cell carcinoma.

Nat Med 2020 10 5;26(10):1519-1530. Epub 2020 Oct 5.

Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Insights into the role of the tumor suppressor pVHL in oxygen sensing motivated the testing of drugs that target the transcription factor HIF or HIF-responsive growth factors, such as VEGF, for the treatment of cancers caused by VHL inactivation, such as clear-cell renal cell carcinoma (ccRCC). Multiple VEGF inhibitors are now approved for the treatment of ccRCC, and a HIF2α inhibitor has advanced to phase 3 development for this disease. These inhibitors are now also increasingly combined with immune-checkpoint blockers. In this Perspective, we describe the understanding of the mechanisms of oxygen sensing and hypoxia signaling that resulted in the development of HIF2α-targeted therapies for patients with VHL-associated tumors. We also present future directions for extending the use of these therapies to other cancers.
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http://dx.doi.org/10.1038/s41591-020-1093-zDOI Listing
October 2020

Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle.

Cell Res 2021 01 15;31(1):80-93. Epub 2020 Jul 15.

Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.

Whether glucose is predominantly metabolized via oxidative phosphorylation or glycolysis differs between quiescent versus proliferating cells, including tumor cells. However, how glucose metabolism is coordinated with cell cycle in mammalian cells remains elusive. Here, we report that mammalian cells predominantly utilize the tricarboxylic acid (TCA) cycle in G1 phase, but prefer glycolysis in S phase. Mechanistically, coupling cell cycle with metabolism is largely achieved by timely destruction of IDH1/2, key TCA cycle enzymes, in a Skp2-dependent manner. As such, depleting SKP2 abolishes cell cycle-dependent fluctuation of IDH1 protein abundance, leading to reduced glycolysis in S phase. Furthermore, elevated Skp2 abundance in prostate cancer cells destabilizes IDH1 to favor glycolysis and subsequent tumorigenesis. Therefore, our study reveals a mechanistic link between two cancer hallmarks, aberrant cell cycle and addiction to glycolysis, and provides the underlying mechanism for the coupling of metabolic fluctuation with periodic cell cycle in mammalian cells.
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http://dx.doi.org/10.1038/s41422-020-0372-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852548PMC
January 2021

CDK7 Inhibition Potentiates Genome Instability Triggering Anti-tumor Immunity in Small Cell Lung Cancer.

Cancer Cell 2020 01 26;37(1):37-54.e9. Epub 2019 Dec 26.

Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA.

Cyclin-dependent kinase 7 (CDK7) is a central regulator of the cell cycle and gene transcription. However, little is known about its impact on genomic instability and cancer immunity. Using a selective CDK7 inhibitor, YKL-5-124, we demonstrated that CDK7 inhibition predominately disrupts cell-cycle progression and induces DNA replication stress and genome instability in small cell lung cancer (SCLC) while simultaneously triggering immune-response signaling. These tumor-intrinsic events provoke a robust immune surveillance program elicited by T cells, which is further enhanced by the addition of immune-checkpoint blockade. Combining YKL-5-124 with anti-PD-1 offers significant survival benefit in multiple highly aggressive murine models of SCLC, providing a rationale for new combination regimens consisting of CDK7 inhibitors and immunotherapies.
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http://dx.doi.org/10.1016/j.ccell.2019.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277075PMC
January 2020

The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis.

Genes Dev 2019 12 14;33(23-24):1718-1738. Epub 2019 Nov 14.

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.

More than 90% of small cell lung cancers (SCLCs) harbor loss-of-function mutations in the tumor suppressor gene The canonical function of the gene product, pRB, is to repress the E2F transcription factor family, but pRB also functions to regulate cellular differentiation in part through its binding to the histone demethylase KDM5A (also known as RBP2 or JARID1A). We show that KDM5A promotes SCLC proliferation and SCLC's neuroendocrine differentiation phenotype in part by sustaining expression of the neuroendocrine transcription factor ASCL1. Mechanistically, we found that KDM5A sustains ASCL1 levels and neuroendocrine differentiation by repressing NOTCH2 and NOTCH target genes. To test the role of KDM5A in SCLC tumorigenesis in vivo, we developed a CRISPR/Cas9-based mouse model of SCLC by delivering an adenovirus (or an adeno-associated virus [AAV]) that expresses Cre recombinase and sgRNAs targeting , and into the lungs of Lox-Stop-Lox Cas9 mice. Coinclusion of a KDM5A sgRNA decreased SCLC tumorigenesis and metastasis, and the SCLCs that formed despite the absence of KDM5A had higher NOTCH activity compared to SCLCs. This work establishes a role for KDM5A in SCLC tumorigenesis and suggests that KDM5 inhibitors should be explored as treatments for SCLC.
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http://dx.doi.org/10.1101/gad.328336.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942053PMC
December 2019

HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species.

Sci Signal 2019 10 1;12(601). Epub 2019 Oct 1.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Inactivation of the tumor suppressor gene is the signature initiating event in clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, and causes the accumulation of hypoxia-inducible factor 2α (HIF-2α). HIF-2α inhibitors are effective in some ccRCC cases, but both de novo and acquired resistance have been observed in the laboratory and in the clinic. Here, we identified synthetic lethality between decreased activity of cyclin-dependent kinases 4 and 6 (CDK4/6) and inactivation in two species (human and ) and across diverse human ccRCC cell lines in culture and xenografts. Although HIF-2α transcriptionally induced the CDK4/6 partner cyclin D1, HIF-2α was not required for the increased CDK4/6 requirement of ccRCC cells. Accordingly, the antiproliferative effects of CDK4/6 inhibition were synergistic with HIF-2α inhibition in HIF-2α-dependent ccRCC cells and not antagonistic with HIF-2α inhibition in HIF-2α-independent cells. These findings support testing CDK4/6 inhibitors as treatments for ccRCC, alone and in combination with HIF-2α inhibitors.
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http://dx.doi.org/10.1126/scisignal.aay0482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913182PMC
October 2019

Mutant p53 induces a hypoxia transcriptional program in gastric and esophageal adenocarcinoma.

JCI Insight 2019 08 8;4(15). Epub 2019 Aug 8.

Department of Medical Oncology and.

Despite the propensity for gastric and esophageal adenocarcinomas to select for recurrent missense mutations in TP53, the precise functional consequence of these mutations remains unclear. Here we report that endogenous mRNA and protein levels of mutant p53 were elevated in cell lines and patients with gastric and esophageal cancer. Functional studies showed that mutant p53 was sufficient, but not necessary, for enhancing primary tumor growth in vivo. Unbiased genome-wide transcriptome analysis revealed that hypoxia signaling was induced by mutant p53 in 2 gastric cancer cell lines. Using real-time in vivo imaging, we confirmed that hypoxia reporter activity was elevated during the initiation of mutant p53 gastric cancer xenografts. Unlike HIF co-factor ARNT, HIF1α was required for primary tumor growth in mutant p53 gastric cancer. These findings elucidate the contribution of missense p53 mutations in gastroesophageal malignancy and indicate that hypoxia signaling rather than mutant p53 itself may serve as a therapeutic vulnerability in these deadly set of cancers.
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http://dx.doi.org/10.1172/jci.insight.128439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693823PMC
August 2019

EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance.

Proc Natl Acad Sci U S A 2019 08 2;116(34):16997-17006. Epub 2019 Aug 2.

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden;

Despite the discovery of the oxygen-sensitive regulation of HIFα by the von Hippel-Lindau (VHL) protein, the mechanisms underlying the complex genotype/phenotype correlations in VHL disease remain unknown. Some germline mutations cause familial pheochromocytoma and encode proteins that preserve their ability to down-regulate HIFα. While type 1, 2A, and 2B mutants are defective in regulating HIFα, type 2C mutants encode proteins that preserve their ability to down-regulate HIFα. Here, we identified an oxygen-sensitive function of VHL that is abolished by type 2C mutations. We found that BIM-EL, a proapoptotic BH3-only protein, is hydroxylated by EglN3 and subsequently bound by VHL. VHL mutants fail to bind hydroxylated BIM-EL, regardless of whether they have the ability to bind hydroxylated HIFα or not. VHL binding inhibits BIM-EL phosphorylation by extracellular signal-related kinase (ERK) on serine 69. This causes BIM-EL to escape from proteasomal degradation, allowing it to enhance EglN3-induced apoptosis. BIM-EL was rapidly degraded in cells lacking wild-type VHL or in which EglN3 was inactivated genetically or by lack of oxygen, leading to enhanced cell survival and chemotherapy resistance. Combination therapy using ERK inhibitors, however, resensitizes VHL- and EglN3-deficient cells that are otherwise cisplatin-resistant.
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http://dx.doi.org/10.1073/pnas.1900748116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708352PMC
August 2019

Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate.

Science 2019 03 14;363(6432):1217-1222. Epub 2019 Mar 14.

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.

Oxygen sensing is central to metazoan biology and has implications for human disease. Mammalian cells express multiple oxygen-dependent enzymes called 2-oxoglutarate (OG)-dependent dioxygenases (2-OGDDs), but they vary in their oxygen affinities and hence their ability to sense oxygen. The 2-OGDD histone demethylases control histone methylation. Hypoxia increases histone methylation, but whether this reflects direct effects on histone demethylases or indirect effects caused by the hypoxic induction of the HIF (hypoxia-inducible factor) transcription factor or the 2-OG antagonist 2-hydroxyglutarate (2-HG) is unclear. Here, we report that hypoxia promotes histone methylation in a HIF- and 2-HG-independent manner. We found that the H3K27 histone demethylase KDM6A/UTX, but not its paralog KDM6B, is oxygen sensitive. KDM6A loss, like hypoxia, prevented H3K27 demethylation and blocked cellular differentiation. Restoring H3K27 methylation homeostasis in hypoxic cells reversed these effects. Thus, oxygen directly affects chromatin regulators to control cell fate.
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http://dx.doi.org/10.1126/science.aaw1026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336390PMC
March 2019

Deubiquitinases Maintain Protein Homeostasis and Survival of Cancer Cells upon Glutathione Depletion.

Cell Metab 2019 05 21;29(5):1166-1181.e6. Epub 2019 Feb 21.

Ludwig Cancer Center, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Cells are subjected to oxidative stress during the initiation and progression of tumors, and this imposes selective pressure for cancer cells to adapt mechanisms to tolerate these conditions. Here, we examined the dependency of cancer cells on glutathione (GSH), the most abundant cellular antioxidant. While cancer cell lines displayed a broad range of sensitivities to inhibition of GSH synthesis, the majority were resistant to GSH depletion. To identify cellular pathways required for this resistance, we carried out genetic and pharmacologic screens. Both approaches revealed that inhibition of deubiquitinating enzymes (DUBs) sensitizes cancer cells to GSH depletion. Inhibition of GSH synthesis, in combination with DUB inhibition, led to an accumulation of polyubiquitinated proteins, induction of proteotoxic stress, and cell death. These results indicate that depletion of GSH renders cancer cells dependent on DUB activity to maintain protein homeostasis and cell viability and reveal a potentially exploitable vulnerability for cancer therapy.
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http://dx.doi.org/10.1016/j.cmet.2019.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506399PMC
May 2019

Peptidic degron for IMiD-induced degradation of heterologous proteins.

Proc Natl Acad Sci U S A 2019 02 25;116(7):2539-2544. Epub 2019 Jan 25.

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Womens Hospital, Harvard Medical School, Boston, MA 02215;

Current systems for modulating the abundance of proteins of interest in living cells are powerful tools for studying protein function but differ in terms of their complexity and ease of use. Moreover, no one system is ideal for all applications, and the best system for a given protein of interest must often be determined empirically. The thalidomide-like molecules (collectively called the IMiDs) bind to the ubiquitously expressed cereblon ubiquitin ligase complex and alter its substrate specificity such that it targets the IKZF1 and IKZF3 lymphocyte transcription factors for destruction. Here, we mapped the minimal IMiD-responsive IKZF3 degron and show that this peptidic degron can be used to target heterologous proteins for destruction with IMiDs in a time- and dose-dependent manner in cultured cells grown ex vivo or in vivo.
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http://dx.doi.org/10.1073/pnas.1818109116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377458PMC
February 2019

Cells Lacking the Tumor Suppressor Gene Are Hyperdependent on Aurora B Kinase for Survival.

Cancer Discov 2019 02 29;9(2):230-247. Epub 2018 Oct 29.

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Small cell lung cancer (SCLC) accounts for 15% of lung cancers and is almost always linked to inactivating and mutations. SCLC frequently responds, albeit briefly, to chemotherapy. The canonical function of the gene product RB1 is to repress the E2F transcription factor family. RB1 also plays both E2F-dependent and E2F-independent mitotic roles. We performed a synthetic lethal CRISPR/Cas9 screen in an SCLC cell line that conditionally expresses to identify dependencies that are caused by RB1 loss and discovered that SCLC cell lines are hyperdependent on multiple proteins linked to chromosomal segregation, including Aurora B kinase. Moreover, we show that an Aurora B kinase inhibitor is efficacious in multiple preclinical SCLC models at concentrations that are well tolerated in mice. These results suggest that RB1 loss is a predictive biomarker for sensitivity to Aurora B kinase inhibitors in SCLC and perhaps other cancers. SIGNIFICANCE: SCLC is rarely associated with actionable protooncogene mutations. We did a CRISPR/Cas9-based screen that showed that SCLC are hyperdependent on , likely because both genes control mitotic fidelity, and confirmed that Aurora B kinase inhibitors are efficacious against SCLC tumors in mice at nontoxic doses...
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http://dx.doi.org/10.1158/2159-8290.CD-18-0389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368871PMC
February 2019

BRCA1-IRIS promotes human tumor progression through PTEN blockade and HIF-1α activation.

Proc Natl Acad Sci U S A 2018 10 25;115(41):E9600-E9609. Epub 2018 Sep 25.

Department of Genetics, Harvard Medical School, Boston, MA 02115;

is an established breast and ovarian tumor suppressor gene that encodes multiple protein products whose individual contributions to human cancer suppression are poorly understood. BRCA1-IRIS (also known as "IRIS"), an alternatively spliced product and a chromatin-bound replication and transcription regulator, is overexpressed in various primary human cancers, including breast cancer, lung cancer, acute myeloid leukemia, and certain other carcinomas. Its naturally occurring overexpression can promote the metastasis of patient-derived xenograft (PDX) cells and other human cancer cells in mouse models. The IRIS-driven metastatic mechanism results from IRIS-dependent suppression of phosphatase and tensin homolog () transcription, which in turn perturbs the PI3K/AKT/GSK-3β pathway leading to prolyl hydroxylase-independent HIF-1α stabilization and activation in a normoxic environment. Thus, despite the tumor-suppressing genetic origin of IRIS, its properties more closely resemble those of an oncoprotein that, when spontaneously overexpressed, can, paradoxically, drive human tumor progression.
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http://dx.doi.org/10.1073/pnas.1807112115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187201PMC
October 2018

Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma.

Cell 2018 09 13;175(1):101-116.e25. Epub 2018 Sep 13.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address:

IDH1 mutations are common in low-grade gliomas and secondary glioblastomas and cause overproduction of (R)-2HG. (R)-2HG modulates the activity of many enzymes, including some that are linked to transformation and some that are probably bystanders. Although prior work on (R)-2HG targets focused on 2OG-dependent dioxygenases, we found that (R)-2HG potently inhibits the 2OG-dependent transaminases BCAT1 and BCAT2, likely as a bystander effect, thereby decreasing glutamate levels and increasing dependence on glutaminase for the biosynthesis of glutamate and one of its products, glutathione. Inhibiting glutaminase specifically sensitized IDH mutant glioma cells to oxidative stress in vitro and to radiation in vitro and in vivo. These findings highlight the complementary roles for BCATs and glutaminase in glutamate biosynthesis, explain the sensitivity of IDH mutant cells to glutaminase inhibitors, and suggest a strategy for maximizing the effectiveness of such inhibitors against IDH mutant gliomas.
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http://dx.doi.org/10.1016/j.cell.2018.08.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219629PMC
September 2018

VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma.

Science 2018 07;361(6399):290-295

Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.

Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.
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http://dx.doi.org/10.1126/science.aap8411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154478PMC
July 2018

Autochthonous tumors driven by loss have an ongoing requirement for the RBP2 histone demethylase.

Proc Natl Acad Sci U S A 2018 04 2;115(16):E3741-E3748. Epub 2018 Apr 2.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215;

Inactivation of the retinoblastoma gene () product, pRB, is common in many human cancers. Targeting downstream effectors of pRB that are central to tumorigenesis is a promising strategy to block the growth of tumors harboring loss-of-function mutations. One such effector is retinoblastoma-binding protein 2 (RBP2, also called JARID1A or KDM5A), which encodes an H3K4 demethylase. Binding of pRB to RBP2 has been linked to the ability of pRB to promote senescence and differentiation. Importantly, genetic ablation of RBP2 is sufficient to phenocopy pRB's ability to induce these cellular changes in cell culture experiments. Moreover, germline deletion significantly impedes tumorigenesis in mice. The value of RBP2 as a therapeutic target in cancer, however, hinges on whether loss of RBP2 could block the growth of established tumors as opposed to simply delaying their onset. Here we show that conditional, systemic ablation of RBP2 in tumor-bearing mice is sufficient to slow tumor growth and significantly extend survival without causing obvious toxicity to the host. These findings show that established -null tumors require RBP2 for growth and further credential RBP2 as a therapeutic target in human cancers driven by inactivation.
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http://dx.doi.org/10.1073/pnas.1716029115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910822PMC
April 2018

HIF2 Inhibitor Joins the Kidney Cancer Armamentarium.

Authors:
William G Kaelin

J Clin Oncol 2018 03 31;36(9):908-910. Epub 2018 Jan 31.

William G. Kaelin Jr, Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1200/JCO.2017.77.5254DOI Listing
March 2018

Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma.

Science 2018 Feb 4;359(6377):801-806. Epub 2018 Jan 4.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Immune checkpoint inhibitors targeting the programmed cell death 1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole-exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the gene ( = 0.012), which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-1 or PD-L1 (PD-1 ligand) blockade therapy alone or in combination with anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) therapies ( = 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and -deficient tumors revealed altered transcriptional output in JAK-STAT (Janus kinase-signal transducers and activators of transcription), hypoxia, and immune signaling pathways. loss in ccRCC may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.
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http://dx.doi.org/10.1126/science.aan5951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035749PMC
February 2018

Senator McCain and Our Shared Humanity.

Authors:
William G Kaelin

Am J Med 2018 03 8;131(3):216-217. Epub 2017 Dec 8.

Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; Howard Hughes Medical Institute, Chevy Chase, Md. Electronic address:

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http://dx.doi.org/10.1016/j.amjmed.2017.11.028DOI Listing
March 2018

Climate Change: What Would Lincoln Do?

Authors:
William G Kaelin

JAMA 2017 Aug;318(7):611

Howard Hughes Medical Institute, Chevy Chase, Maryland.

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http://dx.doi.org/10.1001/jama.2017.6999DOI Listing
August 2017

The VHL Tumor Suppressor Gene: Insights into Oxygen Sensing and Cancer.

Authors:
William G Kaelin

Trans Am Clin Climatol Assoc 2017 ;128:298-307

BOSTON, MASSACHUSETTS.

Mammalian cells sense changes in oxygen and transduce that information into adaptive changes in gene expression using a conserved pathway that converges on the heterodimeric transcription factor called hypoxia-inducible factor (HIF), which contains a labile alpha subunit and a stable beta subunit. In the presence of oxygen, the alpha subunit is hydroxylated on one (or both) of two highly conserved prolyl residues by an Egg-Laying Defective Nine (EglN) [also called Prolyl Hydroxylase Domain (PHD)] dioxygenase, which recruits an ubiquitin ligase complex containing the tumor suppressor gene product. Germline mutations cause von Hippel-Lindau (VHL) disease, which manifest as angiogenic tumors such as hemangioblastomas and kidney cancers. Somatic inactivation and deregulation of HIF (especially HIF2α) drives sporadic kidney cancers and an HIF2α inhibitor is showing promise for this disease. , and polymorphisms have been linked to familial polycythemia and adaptation to high altitude. Orally available EglN inhibitors are being developed for the treatment of anemia and ischemic diseases.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525432PMC
May 2018

HIF activation causes synthetic lethality between the tumor suppressor and the histone methyltransferase.

Sci Transl Med 2017 07;9(398)

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.

Inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL) is the signature lesion in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). pVHL loss causes the transcriptional activation of hypoxia-inducible factor (HIF) target genes, including many genes that encode histone lysine demethylases. Moreover, chromatin regulators are frequently mutated in this disease. We found that ccRCC displays increased H3K27 acetylation and a shift toward mono- or unmethylated H3K27 caused by an HIF-dependent increase in H3K27 demethylase activity. Using a focused short hairpin RNA library, as well as CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9) and a pharmacological inhibitor, we discovered that pVHL-defective ccRCC cells are hyperdependent on the H3K27 methyltransferase EZH1 for survival. Therefore, targeting EZH1 could be therapeutically useful in ccRCC.
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http://dx.doi.org/10.1126/scitranslmed.aal5272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039096PMC
July 2017

The EGLN-HIF O-Sensing System: Multiple Inputs and Feedbacks.

Mol Cell 2017 Jun;66(6):772-779

Howard Hughes Medical Institute, Boston, MA 02215, USA; Dana-Farber Cancer Institute, Boston, MA 02215, USA; Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.

The EGLN (also called PHD) prolyl hydroxylase enzymes and their canonical targets, the HIFα subunits, represent the core of an ancient oxygen-monitoring machinery used by metazoans. In this review, we highlight recent progress in understanding the overlapping versus specific roles of EGLN enzymes and HIF isoforms and discuss how feedback loops based on recently identified noncoding RNAs introduce additional layers of complexity to the hypoxic response. Based on novel interactions identified upstream and downstream of EGLNs, an integrated network connecting oxygen-sensing functions to metabolic and signaling pathways is gradually emerging with broad therapeutic implications.
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http://dx.doi.org/10.1016/j.molcel.2017.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5613951PMC
June 2017

Publish houses of brick, not mansions of straw.

Authors:
William G Kaelin

Nature 2017 05;545(7655):387

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http://dx.doi.org/10.1038/545387aDOI Listing
May 2017

Common pitfalls in preclinical cancer target validation.

Authors:
William G Kaelin

Nat Rev Cancer 2017 07 19;17(7):425-440. Epub 2017 May 19.

Howard Hughes Medical Institute, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.

An alarming number of papers from laboratories nominating new cancer drug targets contain findings that cannot be reproduced by others or are simply not robust enough to justify drug discovery efforts. This problem probably has many causes, including an underappreciation of the danger of being misled by off-target effects when using pharmacological or genetic perturbants in complex biological assays. This danger is particularly acute when, as is often the case in cancer pharmacology, the biological phenotype being measured is a 'down' readout (such as decreased proliferation, decreased viability or decreased tumour growth) that could simply reflect a nonspecific loss of cellular fitness. These problems are compounded by multiple hypothesis testing, such as when candidate targets emerge from high-throughput screens that interrogate multiple targets in parallel, and by a publication and promotion system that preferentially rewards positive findings. In this Perspective, I outline some of the common pitfalls in preclinical cancer target identification and some potential approaches to mitigate them.
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http://dx.doi.org/10.1038/nrc.2017.32DOI Listing
July 2017

Inactivation of the PBRM1 tumor suppressor gene amplifies the HIF-response in VHL-/- clear cell renal carcinoma.

Proc Natl Acad Sci U S A 2017 01 12;114(5):1027-1032. Epub 2017 Jan 12.

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

Most clear cell renal carcinomas (ccRCCs) are initiated by somatic inactivation of the VHL tumor suppressor gene. The VHL gene product, pVHL, is the substrate recognition unit of an ubiquitin ligase that targets the HIF transcription factor for proteasomal degradation; inappropriate expression of HIF target genes drives renal carcinogenesis. Loss of pVHL is not sufficient, however, to cause ccRCC. Additional cooperating genetic events, including intragenic mutations and copy number alterations, are required. Common examples of the former are loss-of-function mutations of the PBRM1 and BAP1 tumor suppressor genes, which occur in a mutually exclusive manner in ccRCC and define biologically distinct subsets of ccRCC. PBRM1 encodes the Polybromo- and BRG1-associated factors-containing complex (PBAF) chromatin remodeling complex component BRG1-associated factor 180 (BAF180). Here we identified ccRCC lines whose ability to proliferate in vitro and in vivo is sensitive to wild-type BAF180, but not a tumor-associated BAF180 mutant. Biochemical and functional studies linked growth suppression by BAF180 to its ability to form a canonical PBAF complex containing BRG1 that dampens the HIF transcriptional signature.
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http://dx.doi.org/10.1073/pnas.1619726114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293026PMC
January 2017

Targeting HIF2 in Clear Cell Renal Cell Carcinoma.

Cold Spring Harb Symp Quant Biol 2016 8;81:113-121. Epub 2016 Dec 8.

Howard Hughes Medical Institute, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 022145.

Inactivation of the von Hippel-Lindau tumor-suppressor protein (pVHL) is the signature "truncal" event in clear cell renal cell carcinoma, which is the most common form of kidney cancer. pVHL is part of a ubiquitin ligase the targets the α subunit of the hypoxia-inducible factor (HIF) transcription factor for destruction when oxygen is available. Preclinical studies strongly suggest that deregulation of HIF, and particularly HIF2, drives pVHL-defective renal carcinogenesis. Although HIF2α was classically considered undruggable, structural and chemical work by Rick Bruick and Kevin Gardner at University of Texas Southwestern laid the foundation for the development of small molecule direct HIF2α antagonists (PT2385 and the related tool compound PT2399) by Peloton Therapeutics that block the dimerization of HIF2α with its partner protein ARNT1. These compounds inhibit clear cell renal cell carcinoma growth in preclinical models, and PT2385 has now entered the clinic. Nonetheless, the availability of such compounds, together with clustered regularly interspaced short palindromic repeat (CRISPR)-based gene editing approaches, has revealed a previously unappreciated heterogeneity among clear cell renal carcinomas and patient-derived xenografts with respect to HIF2 dependence, suggesting that predictive biomarkers will be needed to optimize the use of such agents in the clinic.
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http://dx.doi.org/10.1101/sqb.2016.81.030833DOI Listing
February 2018

On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models.

Nature 2016 11 5;539(7627):107-111. Epub 2016 Sep 5.

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.

Clear cell renal cell carcinoma, the most common form of kidney cancer, is usually linked to inactivation of the pVHL tumour suppressor protein and consequent accumulation of the HIF-2α transcription factor (also known as EPAS1). Here we show that a small molecule (PT2399) that directly inhibits HIF-2α causes tumour regression in preclinical mouse models of primary and metastatic pVHL-defective clear cell renal cell carcinoma in an on-target fashion. pVHL-defective clear cell renal cell carcinoma cell lines display unexpectedly variable sensitivity to PT2399, however, suggesting the need for predictive biomarkers to be developed to use this approach optimally in the clinic.
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http://dx.doi.org/10.1038/nature19795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499381PMC
November 2016
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