Laboratory of Cancer Pharmacogenomics
Welcome to the Laboratory of Cancer Pharmacogenomics under the direction of Principal Investigator Dr. Anurag Singh.
Research in the Laboratory of Cancer Pharmacogenomics focuses on context dependent mitogenic signal transduction networks that drive proliferation and survival of tumor cells. The lab uses orthogonal and integrated approaches, including functional genomics and systems pharmacology to understand global gene regulatory networks that contribute to cancer pathophysiology. Computational methods including linear modeling and hierarchical clustering are used to identify differentially expressed genes and expression modules in major molecular subtypes of lung, pancreatic and colon cancers (see Figure 1). Candidate genes and signaling pathways are then functionally characterized using cellular, biochemical and pharmacological methodologies (see Figure 2). The ultimate aim is to identify candidate therapeutic targets for poor prognosis cancer types.
Current research in the lab is focused on elucidating oncogenic KRAS-dependent transcriptional networks that coordinately regulate inflammation, autophagy and cell survival. We are also interested in contextual variability in these networks based on tissue lineage and genetic background. Through this approach, we have identified a number of attractive candidate therapeutic targets that can be antagonized to promote cancer cell death in a context-dependent manner, such as the kinase TAK1 in colon cancers. Since effective pharmacological targeting of the mutant KRAS protein has proven challenging, a key translational goal is to identify clinically efficacious small molecule inhibitors against critical nodes in oncogenic KRAS signaling networks.
Current research projects in the lab include:
1. Functional and mechanistic elucidation of the KRAS-MEK-TAK1 proinflammatory signaling network in KRAS-dependent colon cancers.
2. Molecular profiling and characterization of KRAS-regulated microRNAs in lung cancer.
3. Identification and validation of novel pro-survival kinases in molecular subtypes of pancreatic cancer.
4. Subtype classifications and therapeutic target identification in NRAS-mutant melanoma.
Anita Mehda, Ph.D.
Kevin Hua, M.D./Ph.D.
William Whipple, B.S.
Current Position: Vanderbilt University M.D./Ph.D. Program.
Synthetic Lethal Interaction of Combined BCL-XL and MEK Inhibition Promotes Tumor Regressions in KRAS Mutant Cancer Models.Corcoran RB, Cheng KA, Hata AN, Faber AC, Ebi H, Coffee EM, Greninger P, Brown RD, Godfrey JT, Cohoon TJ, Song Y, Lifshits E, Hung KE, Shioda T, Dias-Santagata D, Singh A, Settleman J, Benes CH, Mino-Kenudson M, Wong KK, Engelman JA. Cancer Cell. 2013 Jan 14; 23(1):121-128.
Singh A, Sweeney M, Burger A, Yu M, Greninger P, Benes C, Haber DA, Settleman J. TAK1 inhibition promotes apoptosis in KRAS-dependent colon cancers. Cell 2012. Feb 17;148(4):639-50. PMC3291475
Ebi H, Corcoran RB, Singh A, Chen Z, Song Y, Lifshits E, Ryan DP, Meyerhardt JA, Benes C, Settleman J, Wong KK, Cantley LC, Engelman JA. Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers. J Clin Invest. 2011 Oct 10.
Singh, A, Settleman J., EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010 Aug 26;29(34):4741-51.
Singh, A, Settleman J, Oncogenic K-ras “addiction” and synthetic lethality. Cell Cycle 2009. Sep 1;8(17):2676-7.
Singh A, Greninger P, Rhodes D, Koopman L, Violette S, Bardeesy N and Settleman J. A gene expression signature associated with “K-Ras addiction” reveals regulators of EMT and tumor cell survival. Cancer Cell 2009 15(6):489-500. Reviewed in “Therapeutics: Dependent on KRAS” – Nat. Rev. Cancer 2009 7(9):457 and “K-Ras’ Achilles’ heel” – Science Business Exchange 2009 2(23): 4-5. Cited by Martin Fernandez-Zapico: Faculty of 1000 Medicine, 2 Sep 2009. Featured in “2009: Signaling Breakthroughs of the Year” – E.M. Adler, Science Signaling, 5 January 2010.
Montagut C, Sharma SV, Shioda T, McDermott U, Ulman M, Ulkus LE, Dias-Santagata D, Stubbs H, Lee DY, Singh A, Drew L, Haber DA, Settleman J. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008 68(12):4853-61.
Chin TM, Quinlan MP, Singh A, Sequist LV, Lynch TJ, Haber DA, Sharma SV, Settleman J. Reduced Erlotinib sensitivity of epidermal growth factor receptor-mutant non-small cell lung cancer following cisplatin exposure: a cell culture model of second-line erlotinib treatment. Clin Cancer Res. 2008 14(21):6867-76.
Singh A, Boyer JL, Der CJ, Zohn IE. Transformation by a nucleotide-activated P2Y receptor is mediated by activation of Galphai, Galphaq and Rho-dependent signaling pathways. J Mol Signal. 2010 Jul 23;5(1):11.
Campbell PM, Singh A, Williams FJ, Frantz K, Ulku AS, Kelley GG, Der CJ. Genetic and pharmacologic dissection of ras effector utilization in oncogenesis. Methods Enzymol 2005 407:195-217.
Singh A, Karnoub AE, Palmby TR, Lengyel E, Sondek J, and Der CJ. Rac1b, a tumor associated, constitutively active Rac1 splice variant, promotes cellular transformation. Oncogene 2004 23(58): 9369-80. Cited by Dr. Brent Cochran Faculty of 1000 Biology – 20th April 2005.
Luquain C, Singh A, Wang L, Natarajan V, and Morris AJ. Role of phospholipase D in agonist-stimulated lysophosphatidic acid synthesis by ovarian cancer cells. J Lipid Res 2003 .44: 1963-75.
Singh A., S.V. Sharma and J. Settleman. 2009. Epidermal Growth Factor Receptor mutations and sensitivity to selective kinase inhibitors in human lung cancer. Genomics and Pharmacogenomics in Anticancer Drug Development and Clinical Response. Edited by Federico Innocenti.
Singh A., 2013. Deregulated Signaling Networks in Lung Cancer. Systems Biology of Cancer. Edited by Sam Thiagalingam. In press.
Anurag Singh, Ph.D.
Departments of Pharmacology & Experimental Therapeutics and Medicine, Division of Medical Oncology and Hematology
Boston University School of Medicine
72 East Concord St., K 712B
Boston, MA 02118-2526
Will Whipple: firstname.lastname@example.org