DF/HCC Program Affiliation

Cancer Cell Biology, Leader
Lung Cancer

DF/HCC Associations

Member, Center Scientific Council

Research Abstract

Our laboratory is investigating the regulation and biological function of signal transduction pathways in the context of human cancer. We are particularly interested in the role of protein kinase-mediated signaling pathways in human tumorigenesis. There are more than 500 kinases encoded by the human genome and many of these have been implicated in cancer. We are exploring mechanisms of molecularly-targeted cancer therapeutics that influence kinase-mediated signaling pathways that become dysregulated during human tumorigenesis. These efforts have led to the establishment of a link between a novel class of activating EGF receptor mutations in lung cancer and the response to EGF receptor inhibitor drugs in a subset of treated patients. To begin to identify additional genetic determinants of drug response in human cancers, we have established a large collection of human cancer cell lines that we are testing for sensitivity to targeted kinase inhibitors. We have established a high-throughput fully automated screening platform to test these lines for drug sensitivity and to identify biomarkers that can be used clinically to guide treatment. These studies are expected to provide further insights into the "wiring" of a tumor cell, and could lead to the optimization of molecularly targeted therapies.

We are also conducting studies to develop a better understanding of the "Oncogene addiction" phenomenon. Oncogene addiction refers to the acquired dependency of cancer cells on a single cellular pathway for survival or sustained proliferation, despite the fact that such cells have accumulated numerous genetic alterations. Moreover, oncogene addiction may account for the dramatic clinical responses reported in some cancer patients treated with the various targeted kinase inhibitors. However, a molecular mechanism to explain oncogene addiction has been elusive. We have conducted studies that reveal a potential mechanism to explain oncogene addiction that involves a shift in the balance of pro-survival and pro-apoptotic signals in oncogene-dependent cancer cells. We are continuing to pursue the specific nature of signaling pathways that contribute to this phenomenon, which may have important implications for the therapeutic use of targeted kinase inhibitors.

Finally, we are interested in understanding the mechanisms by which cancer cells become resistant to targeted drugs that disrupt signaling pathways. We have developed several in vitro models of drug resistance and we are examining the role of cancer stem cells in the context of both tumor initiation and drug resistance.

Publications

• Haber DA, Settleman J.Cancer: drivers and passengers.Nature 2007 Mar 8;446(7132):145-6.
  17344839
• Mulloy R, Ferrand A, Kim Y, Sordella R, Bell DW, Haber DA, Anderson KS, Settleman J.Epidermal growth factor receptor mutants from human lung cancers exhibit enhanced catalytic activity and increased sensitivity to gefitinib.Cancer Res 2007 Mar 1;67(5):232
  17332364
• Sharma SV, Bell DW, Settleman J, Haber DA.Epidermal growth factor receptor mutations in lung cancer.Nat Rev Cancer 2007 Mar;7(3):169-81.
  17318210
• Sharma SV, Gajowniczek P, Way IP, Lee DY, Jiang J, Yuza Y, Classon M, Haber DA, Settleman J.A common signaling cascade may underlie "addiction" to the Src, BCR-ABL, and EGF receptor oncogenes.Cancer Cell 2006 Nov;10(5):425-35.
  17097564
• Sharma SV, Fischbach MA, Haber DA, Settleman J."Oncogenic Shock": Explaining Oncogene Addiction through Differential Signal Attenuation.Clin Cancer Res 2006 Jul 15;12(14):4392s-5s.
  16857816
• Smolen GA, Sordella R, Muir B, Mohapatra G, Barmettler A, Archibald H, Kim WJ, Okimoto RA, Bell DW, Sgroi DC, Christensen JG, Settleman J, Haber DA.Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine ki
  16461907
• Sordella R, Bell DW, Haber DA, Settleman J.Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways.Science 2004 Aug 20;305(5687):1163-7.
  15284455
• Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA.Activating mutations in the epidermal growth factor receptor underlying responsiveness
  15118073
• Lu Y, Settleman J.The Drosophila Pkn protein kinase is a Rho/Rac effector target required for dorsal closure during embryogenesis.Genes Dev 1999 May 1;13(9):1168-80.
  10323867
• Barrett K, Leptin M, Settleman J.The Rho GTPase and a putative RhoGEF mediate a signaling pathway for the cell shape changes in Drosophila gastrulation.Cell 1997 Dec 26;91(7):905-15.
  9428514