I am a physician scientist and medical oncologist at Stanford University. My laboratory operates at the intersection of functional genomics and chemical biology, with the goal of advancing novel molecular mechanisms of cancer inhibition to clinical use. We aim to 1) leverage phenotypic screening and functional genomics to determine novel anti-cancer mechanisms of small molecules, 2) develop new targeted therapy approaches against solid tumors, and 3) build a comprehensive community resource for drug repurposing discovery.

Clinical Focus

  • Medical Oncology

Academic Appointments

Administrative Appointments

  • The Josephine Q. Berry Faculty Scholar in Cancer Research, Stanford University (2022 - Present)

Honors & Awards

  • Shmunis Family Innovation Award in Cancer Therapeutics, Stanford Cancer Institute (2023)
  • The 20 under 40 in BioPharma, Endpoints News (2020)
  • Young Physician Scientist Award, American Society for Clinical Investigation (2020)
  • K08 Clinical Scientist Research Career Development Award, National Cancer Institute (2018)
  • Next Generation Award, Broad Institute (2018)
  • Young Investigator Award, American Society of Clinical Oncology (2014)
  • Howard Hughes Medical Institute Research Fellowship, HHMI (2005)
  • Alexandra J. Miliotis Research Fellowship in Pediatric Oncology, Miliotis Foundation (2004)
  • Phi Beta Kappa, Harvard University (2003)
  • Thomas Temple Hoopes Prize for outstanding senior thesis, Harvard University (2003)

Professional Education

  • Board Certification: American Board of Internal Medicine, Internal Medicine (2023)
  • Board Certification: American Board of Internal Medicine, Hematology (2014)
  • Board Certification: American Board of Internal Medicine, Medical Oncology (2014)
  • Fellowship: Dana Farber Cancer Institute Hematology Oncology Fellowship (2014) MA
  • Residency: Massachusetts General Hospital Internal Medicine Residency (2011) MA
  • Medical Education: Harvard Medical School (2008) MA
  • AB, Harvard University, Biochemical Sciences (2003)

Current Research and Scholarly Interests

Our laboratory operates at the intersection of functional genomics and chemical biology, with the goal of advancing novel molecular mechanisms of cancer inhibition to clinical use. We aim to 1) leverage phenotypic screening and functional genomics to determine novel anti-cancer mechanisms of small molecules, 2) develop new targeted therapy approaches against solid tumors, and 3) build a comprehensive community resource for drug repurposing discovery.

2023-24 Courses

Stanford Advisees

Graduate and Fellowship Programs

All Publications

  • RAS/RAF co-mutation and ERBB2 copy number modulates HER2 heterogeneity and responsiveness to HER2-directed therapy in colorectal cancer. Clinical cancer research : an official journal of the American Association for Cancer Research Singh, H., Sahgal, P., Kapner, K., Corsello, S. M., Gupta, H., Gujrathi, R., Li, Y. Y., Cherniack, A. D., El Alam, R., Kerfoot, J., Andrews, E., Lee, A., Nambiar, C., Hannigan, A. M., Remland, J., Brais, L., Leahy, M. E., Rubinson, D. A., Schlechter, B. L., Meyerson, M., Kuang, Y., Paweletz, C. P., Lee, J. K., Quintanilha, J. C., Aguirre, A. J., Perez, K. J., Huffman, B. M., Rossi, H., Abrams, T. A., Kabraji, S., Trusolino, L., Bertotti, A., Sicinska, E. T., Parikh, A. R., Wolpin, B. M., Schrock, A. B., Giannakis, M., Ng, K., Meyerhardt, J. A., Hornick, J. L., Sethi, N. S., Cleary, J. M. 2024


    ERBB2 amplified colorectal cancer (CRC) is a distinct molecular subtype with expanding treatments. Implications of concurrent oncogenic RAS/RAF alterations are not known.Dana-Farber and Foundation Medicine Inc. CRC cohorts with genomic profiling were used to identify ERBB2 amplified cases (Dana-Farber, n = 47/2,729 [1.7%]; FMI, n = 1857/49,839 [3.7%]). Outcomes of patients receiving HER2-directed therapies are reported (Dana-Farber, n = 9; Flatiron Health-Foundation Medicine clinicogenomic database, FH-FMI CGDB, n = 38). Multi-site HER2 immunohistochemistry and genomic profiling were performed to understand HER2 intratumoral and interlesional heterogeneity. The impact of concurrent RAS co-mutations on the effectiveness of HER2-directed therapies were studied in isogenic CRC cell lines and xenografts.ERBB2 amplifications are enriched in left-sided CRC. 20% of ERBB2 amplified CRCs have co-occurring oncogenic RAS/RAF alterations. While RAS/RAF wild-type CRC typically have clonal ERBB2 amplification, CRCs with co-occurring RAS/RAF alterations have lower level ERRB2 amplification, higher intratumoral heterogeneity, and interlesional ERBB2 discordance. These distinct genomic patterns lead to differential responsiveness and patterns of resistance to HER2-directed therapy. ERBB2 amplified CRC with RAS/RAF alterations are resistant to trastuzumab-based combinations, such as trastuzumab/tucatinib, but retain sensitivity to trastuzumab deruxtecan in in vitro and murine models. Trastuzumab deruxtecan shows clinical efficacy in cases with high-level ERBB2 amplified RAS/RAF co-altered CRC.Co-occurring RAS/RAF alterations define a unique subtype of ERBB2 amplified CRC that has increased intratumoral heterogeneity, interlesional discordance and resistance to trastuzumab-based combinations. Further examination of trastuzumab deruxtecan in this previously understudied cohort of ERBB2 amplified CRC is warranted.

    View details for DOI 10.1158/1078-0432.CCR-23-2581

    View details for PubMedID 38345769

  • Proteomics-Based Discovery of First-in-Class Chemical Probes for Programmed Cell Death Protein 2 (PDCD2). Angewandte Chemie (International ed. in English) Ji, W., Byun, W. S., Lu, W., Zhu, X., Donovan, K. A., Dwyer, B., Che, J., Yuan, L., Abulaiti, X., Corsello, S. M., Fischer, E. S., Zhang, T., Gray, N. S. 2023: e202308292


    Chemical probes are essential tools for understanding biological systems and for credentialing potential biomedical targets. Programmed cell death 2 (PDCD2) is a member of the B-cell lymphoma 2 (Bcl-2) family of proteins, which are critical regulators of apoptosis. Here we report the discovery and characterization of 10e, a first-in-class small molecule degrader of PDCD2. We discovered PDCD2 degrader by serendipity using a chemical proteomics approach in contrast to the conventional approach for making bivalent degraders starting from a known binding ligand targeting the protein of interest. Using 10e as a pharmacological probe, we demonstrate that PDCD2 functions as a critical regulator of cell growth by modulating the progression of the cell cycle in T lymphoblasts. Our work provides a useful pharmacological probe for investigating PDCD2 function and highlights using chemical proteomics to discover selective small molecule degraders of unanticipated targets.

    View details for DOI 10.1002/anie.202308292

    View details for PubMedID 37658265

  • Structure-Based Design of Y-Shaped Covalent TEAD Inhibitors. Journal of medicinal chemistry Lu, W., Fan, M., Ji, W., Tse, J., You, I., Ficarro, S. B., Tavares, I., Che, J., Kim, A. Y., Zhu, X., Boghossian, A., Rees, M. G., Ronan, M. M., Roth, J. A., Hinshaw, S. M., Nabet, B., Corsello, S. M., Kwiatkowski, N., Marto, J. A., Zhang, T., Gray, N. S. 2023


    Transcriptional enhanced associate domain (TEAD) proteins together with their transcriptional coactivator yes-associated protein (YAP) and transcriptional coactivator with the PDZ-binding motif (TAZ) are important transcription factors and cofactors that regulate gene expression in the Hippo pathway. In mammals, the TEAD families have four homologues: TEAD1 (TEF-1), TEAD2 (TEF-4), TEAD3 (TEF-5), and TEAD4 (TEF-3). Aberrant expression and hyperactivation of TEAD/YAP signaling have been implicated in a variety of malignancies. Recently, TEADs were recognized as being palmitoylated in cells, and the lipophilic palmitate pocket has been successfully targeted by both covalent and noncovalent ligands. In this report, we present the medicinal chemistry effort to develop MYF-03-176 (compound 22) as a selective, cysteine-covalent TEAD inhibitor. MYF-03-176 (compound 22) significantly inhibits TEAD-regulated gene expression and proliferation of the cell lines with TEAD dependence including those derived from mesothelioma and liposarcoma.

    View details for DOI 10.1021/acs.jmedchem.2c01548

    View details for PubMedID 36946421

  • Programmatic Precision Oncology Decision Support for Patients With Gastrointestinal Cancer. JCO precision oncology Keller, R. B., Mazor, T., Sholl, L., Aguirre, A. J., Singh, H., Sethi, N., Bass, A., Nagaraja, A. K., Brais, L. K., Hill, E., Hennessey, C., Cusick, M., Del Vecchio Fitz, C., Zwiesler, Z., Siegel, E., Ovalle, A., Trukhanov, P., Hansel, J., Shapiro, G. I., Abrams, T. A., Biller, L. H., Chan, J. A., Cleary, J. M., Corsello, S. M., Enzinger, A. C., Enzinger, P. C., Mayer, R. J., McCleary, N. J., Meyerhardt, J. A., Ng, K., Patel, A. K., Perez, K. J., Rahma, O. E., Rubinson, D. A., Wisch, J. S., Yurgelun, M. B., Hassett, M. J., MacConaill, L., Schrag, D., Cerami, E., Wolpin, B. M., Nowak, J. A., Giannakis, M. 2023; 7: e2200342


    With the growing number of available targeted therapeutics and molecular biomarkers, the optimal care of patients with cancer now depends on a comprehensive understanding of the rapidly evolving landscape of precision oncology, which can be challenging for oncologists to navigate alone.We developed and implemented a precision oncology decision support system, GI TARGET, (Gastrointestinal Treatment Assistance Regarding Genomic Evaluation of Tumors) within the Gastrointestinal Cancer Center at the Dana-Farber Cancer Institute. With a multidisciplinary team, we systematically reviewed tumor molecular profiling for GI tumors and provided molecularly informed clinical recommendations, which included identifying appropriate clinical trials aided by the computational matching platform MatchMiner, suggesting targeted therapy options on or off the US Food and Drug Administration-approved label, and consideration of additional or orthogonal molecular testing.We reviewed genomic data and provided clinical recommendations for 506 patients with GI cancer who underwent tumor molecular profiling between January and June 2019 and determined follow-up using the electronic health record. Summary reports were provided to 19 medical oncologists for patients with colorectal (n = 198, 39%), pancreatic (n = 124, 24%), esophagogastric (n = 67, 13%), biliary (n = 40, 8%), and other GI cancers. We recommended ≥ 1 precision medicine clinical trial for 80% (406 of 506) of patients, leading to 24 enrollments. We recommended on-label and off-label targeted therapies for 6% (28 of 506) and 25% (125 of 506) of patients, respectively. Recommendations for additional or orthogonal testing were made for 42% (211 of 506) of patients.The integration of precision medicine in routine cancer care through a dedicated multidisciplinary molecular tumor board is scalable and sustainable, and implementation of precision oncology recommendations has clinical utility for patients with cancer.

    View details for DOI 10.1200/PO.22.00342

    View details for PubMedID 36634297

  • RNF43 G659fs is an oncogenic and immune- modulating colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition. Giannakis, M., Fang, L., Ford-Roshon, D., Russo, M., O'Brien, C., Xiong, X., Gurjao, C., Grandclaudon, M., Raghavan, S., Corsello, S. M., Carr, S. A., Udeshi, N., Berstler, J., Sicinska, E., Ng, K. AMER ASSOC CANCER RESEARCH. 2022
  • Virtual screening for small-molecule pathway regulators by image-profile matching. Cell systems Rohban, M. H., Fuller, A. M., Tan, C., Goldstein, J. T., Syangtan, D., Gutnick, A., DeVine, A., Nijsure, M. P., Rigby, M., Sacher, J. R., Corsello, S. M., Peppler, G. B., Bogaczynska, M., Boghossian, A., Ciotti, G. E., Hands, A. T., Mekareeya, A., Doan, M., Gale, J. P., Derynck, R., Turbyville, T., Boerckel, J. D., Singh, S., Kiessling, L. L., Schwarz, T. L., Varelas, X., Wagner, F. F., Kafri, R., Eisinger-Mathason, T. S., Carpenter, A. E. 2022


    Identifying the chemical regulators of biological pathways is a time-consuming bottleneck in developing therapeutics and research compounds. Typically, thousands to millions of candidate small molecules are tested in target-based biochemical screens or phenotypic cell-based screens, both expensive experiments customized to each disease. Here, our uncustomized, virtual, profile-based screening approach instead identifies compounds that match to pathways based on the phenotypic information in public cell image data, created using the Cell Painting assay. Our straightforward correlation-based computational strategy retrospectively uncovered the expected, known small-molecule regulators for 32% of positive-control gene queries. In prospective, discovery mode, we efficiently identified new compounds related to three query genes and validated them in subsequent gene-relevant assays, including compounds that phenocopy or pheno-oppose YAP1 overexpression and kill a Yap1-dependent sarcoma cell line. This image-profile-based approach could replace many customized labor- and resource-intensive screens and accelerate the discovery of biologically and therapeutically useful compounds.

    View details for DOI 10.1016/j.cels.2022.08.003

    View details for PubMedID 36057257

  • Discovery of potent and selective CSNK1A1 inhibitors for solid tumor therapy Corsello, S. M., Zhang, H., Rupaimoole, R., Schulze, V. K., Lemos, C., Handing, K. B., Orsi, D. L., Shekhar, M., Sack, U., Christian, S., Bone, W., Humeidi, R., Colgan, W., Hoyt, S., Cherniack, A., Schroder, J., Kaulfuss, S., Brzezinka, K., von Ahsen, O., Mengel, A., Hillig, R. C., Suelzle, D., Mortier, J., Harrington, C., Nagari, R., Wierzbinska, J., Chiang, D., Beckmann, G., Olive, M., Udeshi, N., Apffel, A., Carr, S., Lienau, P., Lechner, C., Boemer, U., Caliman, A., McKinney, D., Wagner, F., Mumberg, D., Bauser, M., Haegebarth, A., Eis, K., Eheim, A., Golub, T. R. AMER ASSOC CANCER RESEARCH. 2022
  • RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition. Nature communications Fang, L., Ford-Roshon, D., Russo, M., O'Brien, C., Xiong, X., Gurjao, C., Grandclaudon, M., Raghavan, S., Corsello, S. M., Carr, S. A., Udeshi, N. D., Berstler, J., Sicinska, E., Ng, K., Giannakis, M. 2022; 13 (1): 3181


    The RNF43_p.G659fs mutation occurs frequently in colorectal cancer, but its function remains poorly understood and there are no specific therapies directed against this alteration. In this study, we find that RNF43_p.G659fs promotes cell growth independent of Wnt signaling. We perform a drug repurposing library screen and discover that cells with RNF43_p.G659 mutations are selectively killed by inhibition of PI3K signaling. PI3K/mTOR inhibitors yield promising antitumor activity in RNF43659mut isogenic cell lines and xenograft models, as well as in patient-derived organoids harboring RNF43_p.G659fs mutations. We find that RNF43659mut binds p85 leading to increased PI3K signaling through p85 ubiquitination and degradation. Additionally, RNA-sequencing of RNF43659mut isogenic cells reveals decreased interferon response gene expression, that is reversed by PI3K/mTOR inhibition, suggesting that RNF43659mut may alter tumor immunity. Our findings suggest a therapeutic application for PI3K/mTOR inhibitors in treating RNF43_p.G659fs mutant cancers.

    View details for DOI 10.1038/s41467-022-30794-7

    View details for PubMedID 35676246

  • Copper induces cell death by targeting lipoylated TCA cycle proteins. Science (New York, N.Y.) Tsvetkov, P., Coy, S., Petrova, B., Dreishpoon, M., Verma, A., Abdusamad, M., Rossen, J., Joesch-Cohen, L., Humeidi, R., Spangler, R. D., Eaton, J. K., Frenkel, E., Kocak, M., Corsello, S. M., Lutsenko, S., Kanarek, N., Santagata, S., Golub, T. R. 2022; 375 (6586): 1254-1261


    Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.

    View details for DOI 10.1126/science.abf0529

    View details for PubMedID 35298263

  • RNF43 G659fs is an oncogenic mutation in colorectal cancer and sensitizes tumor cells to PI3K/mTOR inhibition. Fang, L., Ford-Roshon, D., Russo, M., O'Brien, C., Gurjao, C., Grandclaudon, M., Corsello, S. M., Raghavan, S., Udeshi, N., Berstler, J., Sicinska, E., Ng, K., Giannakis, M. AMER ASSOC CANCER RESEARCH. 2021
  • Adenosine receptor antagonists exhibit potent and selective off-target killing of FOXA1-high cancers Corsello, S. M., Spangler, R. D., Humeidi, R., Harrington, C. N., Nagari, R. T., Singh, R., Wang, V., Kocak, M., Rossen, J., Madec, A., Dumont, N., Golub, T. R. AMER ASSOC CANCER RESEARCH. 2020
  • The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K NATURE Slabicki, M., Kozicka, Z., Petzold, G., Li, Y., Manojkumar, M., Bunker, R. D., Donovan, K. A., Sievers, Q. L., Koeppel, J., Suchyta, D., Sperling, A. S., Fink, E. C., Gasser, J. A., Wang, L. R., Corsello, S. M., Sellar, R. S., Jan, M., Gillingham, D., Scholl, C., Frohling, S., Golub, T. R., Fischer, E. S., Thoma, N. H., Ebert, B. L. 2020; 585 (7824): 293-+


    Molecular glue compounds induce protein-protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation1. Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets2. They are clinically effective and highly sought-after, but have thus far only been discovered serendipitously. Here, through systematically mining databases for correlations between the cytotoxicity of 4,518 clinical and preclinical small molecules and the expression levels of E3 ligase components across hundreds of human cancer cell lines3-5, we identify CR8-a cyclin-dependent kinase (CDK) inhibitor6-as a compound that acts as a molecular glue degrader. The CDK-bound form of CR8 has a solvent-exposed pyridyl moiety that induces the formation of a complex between CDK12-cyclin K and the CUL4 adaptor protein DDB1, bypassing the requirement for a substrate receptor and presenting cyclin K for ubiquitination and degradation. Our studies demonstrate that chemical alteration of surface-exposed moieties can confer gain-of-function glue properties to an inhibitor, and we propose this as a broader strategy through which target-binding molecules could be converted into molecular glues.

    View details for DOI 10.1038/s41586-020-2374-x

    View details for Web of Science ID 000537663800004

    View details for PubMedID 32494016

    View details for PubMedCentralID PMC7486275

  • Discovering the anticancer potential of non-oncology drugs by systematic viability profiling NATURE CANCER Corsello, S. M., Nagari, R. T., Spangler, R. D., Rossen, J., Kocak, M., Bryan, J. G., Humeidi, R., Peck, D., Wu, X., Tang, A. A., Wang, V. M., Bender, S. A., Lemire, E., Narayan, R., Montgomery, P., Ben-David, U., Garvie, C. W., Chen, Y., Rees, M. G., Lyons, N. J., McFarland, J. M., Wong, B. T., Wang, L., Dumont, N., O'Hearn, P. J., Stefan, E., Doench, J. G., Harrington, C. N., Greulich, H., Meyerson, M., Vazquez, F., Subramanian, A., Roth, J. A., Bittker, J. A., Boehm, J. S., Mader, C. C., Tsherniak, A., Golub, T. R. 2020; 1 (2): 235-+


    Anti-cancer uses of non-oncology drugs have occasionally been found, but such discoveries have been serendipitous. We sought to create a public resource containing the growth inhibitory activity of 4,518 drugs tested across 578 human cancer cell lines. We used PRISM, a molecular barcoding method, to screen drugs against cell lines in pools. An unexpectedly large number of non-oncology drugs selectively inhibited subsets of cancer cell lines in a manner predictable from the cell lines' molecular features. Our findings include compounds that killed by inducing PDE3A-SLFN12 complex formation; vanadium-containing compounds whose killing depended on the sulfate transporter SLC26A2; the alcohol dependence drug disulfiram, which killed cells with low expression of metallothioneins; and the anti-inflammatory drug tepoxalin, which killed via the multi-drug resistance protein ABCB1. The PRISM drug repurposing resource ( is a starting point to develop new oncology therapeutics, and more rarely, for potential direct clinical translation.

    View details for DOI 10.1038/s43018-019-0018-6

    View details for Web of Science ID 000608021200016

    View details for PubMedID 32613204

    View details for PubMedCentralID PMC7328899

  • Intrinsic Resistance to Immune Checkpoint Blockade in a Mismatch Repair-Deficient Colorectal Cancer CANCER IMMUNOLOGY RESEARCH Gurjao, C., Liu, D., Hofree, M., AlDubayan, S. H., Wakiro, I., Su, M., Felt, K., Gjini, E., Brais, L. K., Rotem, A., Rosenthal, M. H., Rozenblatt-Rosen, O., Rodig, S., Ng, K., Van Allen, E. M., Corsello, S. M., Ogino, S., Regev, A., Nowak, J. A., Giannakis, M. 2019; 7 (8): 1230-1236


    Immunotherapy with checkpoint inhibitors, such as the programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab, are effective in a variety of tumors, yet not all patients respond. Tumor microsatellite instability-high (MSI-H) has emerged as a biomarker of response to checkpoint blockade, leading to the tissue agnostic approval of pembrolizumab in MSI-H cancers. Here we describe a patient with MSI-H colorectal cancer that was treated with this immune checkpoint inhibitor and exhibited progression of disease. We examined this intrinsic resistance through genomic, transcriptional, and pathologic characterization of the patient's tumor and the associated immune microenvironment. The tumor had typical MSI-H molecular features, including a high neoantigen load. We also identified biallelic loss of the gene for β2-microglobulin (B2M), whose product is critical for antigen presentation. Immune infiltration deconvolution analysis of bulk transcriptome data from this anti-PD-1-resistant tumor and hundreds of other colorectal cancer specimens revealed a high natural killer cell and M2 macrophage infiltration in the patient's cancer. This was confirmed by single-cell transcriptome analysis and multiplex immunofluorescence. Our study provides insight into resistance in MSI-H tumors and suggests immunotherapeutic strategies in additional genomic contexts of colorectal cancer.

    View details for DOI 10.1158/2326-6066.CIR-18-0683

    View details for Web of Science ID 000478015500002

    View details for PubMedID 31217164

    View details for PubMedCentralID PMC6679789

  • Novel cell line barcoding method reveals tepoxalin as a selective drug against MDR1-high tumor cells Corsello, S. M., Spangler, R. D., Nagari, R. T., Kocak, M., Rossen, J., O'Hearn, P., Roth, J., Gonzalez, A., Dumont, N., Doench, J., Boehm, J. S., Vazquez, F., Tsherniak, A., Golub, T. R. AMER ASSOC CANCER RESEARCH. 2019
  • Characterization of intratumoral heterogeneity in drug sensitivity and modeling of drug combination effects using subclonal cell populations derived from a single breast cancer cell line Kuiken, H. J., Friend, C. M., Corsello, S. M., Mader, C. C., Brugge, J. S. AMER ASSOC CANCER RESEARCH. 2019
  • Structure of Casein Kinase 1A as a Tool in Rational Drug Design. Handing, K., Corsello, S. M., Stefan, E., Castan, I., Nagari, R., Gelles-Watnick, S., Gale, J., Kaushik, V., Hilgraf, R., Mulrooney, C., Emmith, K., Lemke, C., Garvie, C., Golub, T. R. WILEY. 2018: 199-200
  • A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles CELL Subramanian, A., Narayan, R., Corsello, S. M., Peck, D. D., Natoli, T. E., Lu, X., Gould, J., Davis, J. F., Tubelli, A. A., Asiedu, J. K., Lahr, D. L., Hirschman, J. E., Liu, Z., Donahue, M., Julian, B., Khan, M., Wadden, D., Smith, I. C., Lam, D., Liberzon, A., Toder, C., Bagul, M., Orzechowski, M., Enache, O. M., Piccioni, F., Johnson, S. A., Lyons, N. J., Berger, A. H., Shamji, A. F., Brooks, A. N., Vrcic, A., Flynn, C., Rosains, J., Takeda, D. Y., Hu, R., Davison, D., Lamb, J., Ardlie, K., Hogstrom, L., Greenside, P., Gray, N. S., Clemons, P. A., Silver, S., Wu, X., Zhao, W., Read-Button, W., Wu, X., Haggarty, S. J., Ronco, L. V., Boehm, J. S., Schreiber, S. L., Doench, J. G., Bittker, J. A., Root, D. E., Wong, B., Golub, T. R. 2017; 171 (6): 1437-+


    We previously piloted the concept of a Connectivity Map (CMap), whereby genes, drugs, and disease states are connected by virtue of common gene-expression signatures. Here, we report more than a 1,000-fold scale-up of the CMap as part of the NIH LINCS Consortium, made possible by a new, low-cost, high-throughput reduced representation expression profiling method that we term L1000. We show that L1000 is highly reproducible, comparable to RNA sequencing, and suitable for computational inference of the expression levels of 81% of non-measured transcripts. We further show that the expanded CMap can be used to discover mechanism of action of small molecules, functionally annotate genetic variants of disease genes, and inform clinical trials. The 1.3 million L1000 profiles described here, as well as tools for their analysis, are available at

    View details for DOI 10.1016/j.cell.2017.10.049

    View details for Web of Science ID 000417362700023

    View details for PubMedID 29195078

  • Assigning clinical meaning to somatic and germ-line whole-exome sequencing data in a prospective cancer precision medicine study GENETICS IN MEDICINE Ghazani, A. A., Oliver, N. M., Pierre, J., Garofalo, A., Rainville, I. R., Hiller, E., Treacy, D. J., Rojas-Rudilla, V., Wood, S., Bair, E., Parello, M., Huang, F., Giannakis, M., Wilson, F. H., Stover, E. H., Corsello, S. M., Nguyen, T., Rana, H. Q., Church, A. J., Lowenstein, C., Cibulskis, C., Amin-Mansour, A., Heng, J., Brais, L., Santos, A., Bauer, P., Waldron, A., Lo, P., Gorman, M., Lydon, C. A., Welch, M., McNamara, P., Gabriel, S., Sholl, L. M., Lindeman, N. I., Garber, J. E., Joffe, S., Van Allen, E. M., Gray, S. W., Janne, P. A., Garraway, L. A., Wagle, N. 2017; 19 (7): 787-795


    Implementing cancer precision medicine in the clinic requires assessing the therapeutic relevance of genomic alterations. A main challenge is the systematic interpretation of whole-exome sequencing (WES) data for clinical care.One hundred sixty-five adults with metastatic colorectal and lung adenocarcinomas were prospectively enrolled in the CanSeq study. WES was performed on DNA extracted from formalin-fixed paraffin-embedded tumor biopsy samples and matched blood samples. Somatic and germ-line alterations were ranked according to therapeutic or clinical relevance. Results were interpreted using an integrated somatic and germ-line framework and returned in accordance with patient preferences.At the time of this analysis, WES had been performed and results returned to the clinical team for 165 participants. Of 768 curated somatic alterations, only 31% were associated with clinical evidence and 69% with preclinical or inferential evidence. Of 806 curated germ-line variants, 5% were clinically relevant and 56% were classified as variants of unknown significance. The variant review and decision-making processes were effective when the process was changed from that of a Molecular Tumor Board to a protocol-based approach.The development of novel interpretive and decision-support tools that draw from scientific and clinical evidence will be crucial for the success of cancer precision medicine in WES studies.Genet Med advance online publication 26 January 2017.

    View details for DOI 10.1038/gim.2016.191

    View details for Web of Science ID 000405385000011

    View details for PubMedID 28125075

  • The Drug Repurposing Hub: a next-generation drug library and information resource NATURE MEDICINE Corsello, S. M., Bittker, J. A., Liu, Z., Gould, J., McCarren, P., Hirschman, J. E., Johnston, S. E., Vrcic, A., Wong, B., Khan, M., Asiedu, J., Narayan, R., Mader, C. C., Subramanian, A., Golub, T. R. 2017; 23 (4): 405-+

    View details for DOI 10.1038/nm.4306

    View details for Web of Science ID 000398768100005

    View details for PubMedID 28388612

    View details for PubMedCentralID PMC5568558

  • Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles CANCER DISCOVERY Kim, E., Ilic, N., Shrestha, Y., Zou, L., Kamburov, A., Zhu, C., Yang, X., Lubonja, R., Tran, N., Nguyen, C., Lawrence, M. S., Piccioni, F., Bagul, M., Doench, J. G., Chouinard, C. R., Wu, X., Hogstrom, L., Natoli, T., Tamayo, P., Horn, H., Corsello, S. M., Lage, K., Root, D. E., Subramanian, A., Golub, T. R., Getz, G., Boehm, J. S., Hahn, W. C. 2016; 6 (7): 714-726


    Cancer genome characterization efforts now provide an initial view of the somatic alterations in primary tumors. However, most point mutations occur at low frequency, and the function of these alleles remains undefined. We have developed a scalable systematic approach to interrogate the function of cancer-associated gene variants. We subjected 474 mutant alleles curated from 5,338 tumors to pooled in vivo tumor formation assays and gene expression profiling. We identified 12 transforming alleles, including two in genes (PIK3CB, POT1) that have not been shown to be tumorigenic. One rare KRAS allele, D33E, displayed tumorigenicity and constitutive activation of known RAS effector pathways. By comparing gene expression changes induced upon expression of wild-type and mutant alleles, we inferred the activity of specific alleles. Because alleles found to be mutated only once in 5,338 tumors rendered cells tumorigenic, these observations underscore the value of integrating genomic information with functional studies.Experimentally inferring the functional status of cancer-associated mutations facilitates the interpretation of genomic information in cancer. Pooled in vivo screen and gene expression profiling identified functional variants and demonstrated that expression of rare variants induced tumorigenesis. Variant phenotyping through functional studies will facilitate defining key somatic events in cancer. Cancer Discov; 6(7); 714-26. ©2016 AACR.See related commentary by Cho and Collisson, p. 694This article is highlighted in the In This Issue feature, p. 681.

    View details for DOI 10.1158/2159-8290.CD-16-0160

    View details for Web of Science ID 000383354500023

    View details for PubMedID 27147599

    View details for PubMedCentralID PMC4930723

  • Reference pharmacologic class analysis for Connectivity Map discovery Corsello, S. M., Narayan, R., Gould, J., Natoli, T. E., Lu, X., Subramanian, A., Golub, T. R. AMER ASSOC CANCER RESEARCH. 2015
  • A Functional Landscape of Resistance to ALK Inhibition in Lung Cancer CANCER CELL Wilson, F. H., Johannessen, C. M., Piccioni, F., Tamayo, P., Kim, J., Van Allen, E. M., Corsello, S. M., Capelletti, M., Calles, A., Butaney, M., Sharifnia, T., Gabriel, S. B., Mesirov, J. P., Hahn, W. C., Engelman, J. A., Meyerson, M., Root, D. E., Jaenne, P. A., Garraway, L. A. 2015; 27 (3): 397-408


    We conducted a large-scale functional genetic study to characterize mechanisms of resistance to ALK inhibition in ALK-dependent lung cancer cells. We identify members of known resistance pathways and additional putative resistance drivers. Among the latter were members of the P2Y purinergic receptor family of G-protein-coupled receptors (P2Y1, P2Y2, and P2Y6). P2Y receptors mediated resistance in part through a protein-kinase-C (PKC)-dependent mechanism. Moreover, PKC activation alone was sufficient to confer resistance to ALK inhibitors, whereas combined ALK and PKC inhibition restored sensitivity. We observed enrichment of gene signatures associated with several resistance drivers (including P2Y receptors) in crizotinib-resistant ALK-rearranged lung tumors compared to treatment-naive controls, supporting a role for these identified mechanisms in clinical ALK inhibitor resistance.

    View details for DOI 10.1016/j.ccell.2015.02.005

    View details for Web of Science ID 000350977200011

    View details for PubMedID 25759024

    View details for PubMedCentralID PMC4398996

  • Identification of AML1-ETO modulators by chemical genomics BLOOD Corsello, S. M., Roti, G., Ross, K. N., Chow, K. T., Galinsky, I., DeAngelo, D. J., Stone, R. M., Kung, A. L., Golub, T. R., Stegmaier, K. 2009; 113 (24): 6193-6205


    Somatic rearrangements of transcription factors are common abnormalities in the acute leukemias. With rare exception, however, the resultant protein products have remained largely intractable as pharmacologic targets. One example is AML1-ETO, the most common translocation reported in acute myeloid leukemia (AML). To identify AML1-ETO modulators, we screened a small molecule library using a chemical genomic approach. Gene expression signatures were used as surrogates for the expression versus loss of the translocation in AML1-ETO-expressing cells. The top classes of compounds that scored in this screen were corticosteroids and dihydrofolate reductase (DHFR) inhibitors. In addition to modulating the AML1-ETO signature, both classes induced evidence of differentiation, dramatically inhibited cell viability, and ultimately induced apoptosis via on-target activity. Furthermore, AML1-ETO-expressing cell lines were exquisitely sensitive to the effects of corticosteroids on cellular viability compared with nonexpressers. The corticosteroids diminished AML1-ETO protein in AML cells in a proteasome- and glucocorticoid receptor-dependent manner. Moreover, these molecule classes demonstrated synergy in combination with standard AML chemotherapy agents and activity in an orthotopic model of AML1-ETO-positive AML. This work suggests a role for DHFR inhibitors and corticosteroids in treating patients with AML1-ETO-positive disease.

    View details for DOI 10.1182/blood-2008-07-166090

    View details for Web of Science ID 000267147100024

    View details for PubMedID 19377049

    View details for PubMedCentralID PMC2699238

  • Does androgen deprivation therapy in men with prostate cancer increase cardiovascular morbidity? NATURE CLINICAL PRACTICE UROLOGY Corsello, S. M., Kantoff, P. W. 2008; 5 (2): 80-81

    View details for DOI 10.1038/ncpuro1015

    View details for Web of Science ID 000252933800009

    View details for PubMedID 18087294

  • Gefitinib induces myeloid differentiation of acute myeloid leukemia BLOOD Stegmaier, K., Corsello, S. M., Ross, K. N., Wong, J. S., DeAngelo, D. J., Golub, T. R. 2005; 106 (8): 2841-2848


    Cure rates for patients with acute myeloid leukemia (AML) remain low despite ever-increasing dose intensity of cytotoxic therapy. In an effort to identify novel approaches to AML therapy, we recently reported a new method of chemical screening based on the modulation of a gene expression signature of interest. We applied this approach to the discovery of AML-differentiation-promoting compounds. Among the compounds inducing neutrophilic differentiation was DAPH1 (4,5-dianilinophthalimide), previously reported to inhibit epidermal growth factor receptor (EGFR) kinase activity. Here we report that the Food and Drug Administration (FDA)-approved EGFR inhibitor gefitinib similarly promotes the differentiation of AML cell lines and primary patient-derived AML blasts in vitro. Gefitinib induced differentiation based on morphologic assessment, nitro-blue tetrazolium reduction, cell-surface markers, genome-wide patterns of gene expression, and inhibition of proliferation at clinically achievable doses. Importantly, EGFR expression was not detected in AML cells, indicating that gefitinib functions through a previously unrecognized EGFR-independent mechanism. These studies indicate that clinical trials testing the efficacy of gefitinib in patients with AML are warranted.

    View details for DOI 10.1182/blood-2005-02-0488

    View details for Web of Science ID 000232466000043

    View details for PubMedID 15998836

    View details for PubMedCentralID PMC1895296