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.
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• 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
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• 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.
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• 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.
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• 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.
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• 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.
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• 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.
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• 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
• Sequist LV, Martins RG, Spigel D, Grunberg SM, Spira A, Janne PA, Joshi VA, McCollum D, Evans TL, Muzikansky A, Kuhlmann GL, Han M, Goldberg JS, Settleman J, Iafrate AJ, Engelman JA, Haber DA, Johnson BE, Lynch TJ.First-Line Gefitinib in Patients With Adv
  18458038
• McDermott U, Iafrate AJ, Gray NS, Shioda T, Classon M, Maheswaran S, Zhou W, Choi HG, Smith SL, Dowell L, Ulkus LE, Kuhlmann G, Greninger P, Christensen JG, Haber DA, Settleman J.Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to an
  18451166
• Quinlan MP, Settleman J.Explaining the preponderance of Kras mutations in human cancer: An isoform-specific function in stem cell expansion.Cell Cycle 2008 Mar 11;7(10).
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• McDermott U, Sharma SV, Settleman J.High-Throughput Lung Cancer Cell Line Screening for Genotype-Correlated Sensitivity to an EGFR Kinase Inhibitor.Methods Enzymol 2008;438:331-41.
  18413259
• Godin-Heymann N, Ulkus L, Brannigan BW, McDermott U, Lamb J, Maheswaran S, Settleman J, Haber DA.The T790M "gatekeeper" mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor.Mol Cancer Ther 2008 Apr;7(4):87
  18413800
• Haigis KM, Kendall KR, Wang Y, Cheung A, Haigis MC, Glickman JN, Niwa-Kawakita M, Sweet-Cordero A, Sebolt-Leopold J, Shannon KM, Settleman J, Giovannini M, Jacks T.Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tum
  18372904
• Baum B, Settleman J, Quinlan MP.Transitions between epithelial and mesenchymal states in development and disease.Semin Cell Dev Biol 2008 Jun;19(3):294-308.
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• Engelman JA, Settleman J.Acquired resistance to tyrosine kinase inhibitors during cancer therapy.Curr Opin Genet Dev 2008 Mar 4.
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• Quinlan MP, Quatela SE, Philips MR, Settleman J.Activated Kras, but not Hras or Nras, may initiate tumors of endodermal origin via stem cell expansion.Mol Cell Biol 2008 Apr;28(8):2659-74.
  18268007
• Bernards A, Settleman J.GEFs in growth factor signaling.Growth Factors 2007 Oct;25(5):355-61.
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• Sharma SV, Settleman J.Oncogene addiction: setting the stage for molecularly targeted cancer therapy.Genes Dev 2007 Dec 15;21(24):3214-31.
  18079171
• McDermott U, Sharma SV, Dowell L, Greninger P, Montagut C, Lamb J, Archibald H, Raudales R, Tam A, Lee D, Rothenberg SM, Supko JG, Sordella R, Ulkus LE, Iafrate AJ, Maheswaran S, Njauw CN, Tsao H, Drew L, Hanke JH, Ma XJ, Erlander MG, Gray NS, Haber DA, S
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• Godin-Heymann N, Bryant I, Rivera MN, Ulkus L, Bell DW, Riese DJ, Settleman J, Haber DA.Oncogenic activity of epidermal growth factor receptor kinase mutant alleles is enhanced by the T790M drug resistance mutation.Cancer Res 2007 Aug 1;67(15):7319-26.
  17671201
• Settleman J, Kurie JM.Drugging the bad "AKT-TOR" to overcome TKI-resistant lung cancer.Cancer Cell 2007 Jul;12(1):6-8.
  17613432
• Riese DJ, Gallo RM, Settleman J.Mutational activation of ErbB family receptor tyrosine kinases: insights into mechanisms of signal transduction and tumorigenesis.Bioessays 2007 Jun;29(6):558-65.
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• Sharma SV, Settleman J.Oncogenic shock: turning an activated kinase against the tumor cell.Cell Cycle 2006 Dec;5(24):2878-80.
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• Emdad L, Lebedeva IV, Su ZZ, Gupta P, Sarkar D, Settleman J, Fisher PB.Combinatorial treatment of non-small-cell lung cancers with gefitinib and Ad.mda-7 enhances apoptosis-induction and reverses resistance to a single therapy.J Cell Physiol 2007 Feb;210(
  17111370
• Verdier V, Chen GC, Settleman J.Rho-kinase regulates tissue morphogenesis via non-muscle myosin and LIM-kinase during Drosophila development.BMC Dev Biol 2006 Aug 1;6(1):38.
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• Haber DA, Bell DW, Sordella R, Kwak EL, Godin-Heymann N, Sharma SV, Lynch TJ, Settleman J.Molecular targeted therapy of lung cancer: EGFR mutations and response to EGFR inhibitors.Cold Spring Harb Symp Quant Biol 2005;70:419-26.
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• Kwak EL, Jankowski J, Thayer SP, Lauwers GY, Brannigan BW, Harris PL, Okimoto RA, Haserlat SM, Driscoll DR, Ferry D, Muir B, Settleman J, Fuchs CS, Kulke MH, Ryan DP, Clark JW, Sgroi DC, Haber DA, Bell DW.Epidermal growth factor receptor kinase domain mut
  16857803
• Lynch TJ, Adjei AA, Bunn PA, Eisen TG, Engelman J, Goss GD, Haber DA, Heymach JV, Jänne PA, Johnson BE, Johnson DH, Lilenbaum RC, Meyerson M, Sandler AB, Sequist LV, Settleman J, Wong KK, Hart CS.Summary statement: novel agents in the treatment of lung ca
  16857812
• Bell DW, Gore I, Okimoto RA, Godin-Heymann N, Sordella R, Mulloy R, Sharma SV, Brannigan BW, Mohapatra G, Settleman J, Haber DA.Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR.Nat Genet 2005 Dec;37
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• Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, Harris PL, Driscoll DR, Fidias P, Lynch TJ, Rabindran SK, McGinnis JP, Wissner A, Sharma SV, Isselbacher KJ, Settleman J, Haber DA.Irreversible inhibitors of the EGF receptor may cir
  15897464
• Song YH, Mirey G, Betson M, Haber DA, Settleman J.The Drosophila ATM ortholog, dATM, mediates the response to ionizing radiation and to spontaneous DNA damage during development.Curr Biol 2004 Aug 10;14(15):1354-9.
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• Yajnik V, Paulding C, Sordella R, McClatchey AI, Saito M, Wahrer DC, Reynolds P, Bell DW, Lake R, van den Heuvel S, Settleman J, Haber DA.DOCK4, a GTPase activator, is disrupted during tumorigenesis.Cell 2003 Mar 7;112(5):673-84.
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• Nolan KM, Barrett K, Lu Y, Hu KQ, Vincent S, Settleman J.Myoblast city, the Drosophila homolog of DOCK180/CED-5, is required in a Rac signaling pathway utilized for multiple developmental processes.Genes Dev 1998 Nov 1;12(21):3337-42.
  9808621
• Wang Y, Falasca M, Schlessinger J, Malstrom S, Tsichlis P, Settleman J, Hu W, Lim B, Prywes R.Activation of the c-fos serum response element by phosphatidyl inositol 3-kinase and rho pathways in HeLa cells.Cell Growth Differ 1998 Jul;9(7):513-22.
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• Maheswaran S, Englert C, Lee SB, Ezzel RM, Settleman J, Haber DA.E1B 55K sequesters WT1 along with p53 within a cytoplasmic body in adenovirus-transformed kidney cells.Oncogene 1998 Apr 23;16(16):2041-50.
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• Hariharan IK, Hu KQ, Asha H, Quintanilla A, Ezzell RM, Settleman J.Characterization of rho GTPase family homologues in Drosophila melanogaster: overexpressing Rho1 in retinal cells causes a late developmental defect.EMBO J 1995 Jan 16;14(2):292-302.
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• Weissbach L, Settleman J, Kalady MF, Snijders AJ, Murthy AE, Yan YX, Bernards A.Identification of a human rasGAP-related protein containing calmodulin-binding motifs.J Biol Chem 1994 Aug 12;269(32):20517-21.
  8051149
• Zhang XF, Settleman J, Kyriakis JM, Takeuchi-Suzuki E, Elledge SJ, Marshall MS, Bruder JT, Rapp UR, Avruch J.Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1.Nature 1993 Jul 22;364(6435):308-13.
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