Takeshi Shimamura, PhD

  • Assistant Professor
  • Molecular Pharmacology and Therapeutics

Investigating the signaling pathways and transcriptome in non-small cell lung cancer (NSCLC) to overcome drug resistance

Lung cancer is the leading cause of cancer-related death in the U.S. ¬In NSCLC, activating EGFR mutations are responsive to reversible EGFR tyrosine kinase inhibitors TKIs, including gefitinib and erlotinib. Despite initial responses, acquired resistance invariably develops and is mediated by the emergence of the secondary T790M mutation and by focal amplification of c-MET, in approximately 50% and 15% of patients, respectively. The resistance mechanisms for the remaining 35% of cases remain elusive. A recent clinical study demonstrated that half of the remaining 35% of these resistant NSCLCs present with an epithelial to mesenchymal transition (EMT) phenotype. However, it remains elusive if EMT is a primary mechanism of TKI resistance. Consequently, we are interested in investigating if EMT is a primary mechanism of EGFR TKI resistance and how EMT modulates signaling cascades leading to the acquired resistance to EGFR TKIs in NSCLC addicted to mutant EGFR for survival and growth. This project was initiated by Dr. Shimamura as a part of Dana-Farber/Harvard Cancer Center Lung SPORE Career development project. Using proteomics and genomics techniques, we are currently investigating if inhibiting specific signaling pathway could re-sensitize the EMT-mediated EGFR TKI resistant NSCLC cells to EGFR TKIs with the ultimate goal of lending further credence to novel early phase clinical trials using the inhibitors. My laboratory is also interested in developing strategies to pharmacologically inhibit mutant KRAS-driven NSCLC. Approximately 15 - 30% of NSCLC patients harbor an oncogenic KRAS mutation associated with resistance to conventional treatment regimens. Oncogenic activation of Kras in the murine lung compartment produces adenocarcinoma and several human lung cancer cell lines harboring mutant KRAS are dependent on KRAS activity for survival; therefore oncogenic mutant KRAS is a highly attractive therapeutic target in NSCLC. However, targeting mutant KRAS with small molecules inhibitors has not proven successful. In collaboration with several laboratories around the world, our laboratory is investigating several novel targets in the subset of NSCLC with mutant KRAS in a hope to find a novel therapeutic strategy. In our laboratory, students are expected to learn techniques and theories in molecular, cellular and cancer biology with specific emphasis in integrating bioinformatics and proteomics to their research projects.

For our most recent publications, please visit http://www.researchgate.net/profile/Takeshi_Shimamura/

Research Areas: Lung cancer, signal transduction, transcription factor, EMT, resistance, EGFR, KRAS, oncogene addiction and mutation.

  • Shimamura,T. Heterogeneity in Tumors and Resistance to EGFR TKI Therapy-Response Cancer research 2016 ;76(10):3111
  • Koyama,S.; Akbay,E. A.; Li,Y. Y.; Aref,A. R.; Skoulidis,F.; Herter-Sprie,G. S.; Buczkowski,K. A.; Liu,Y.; Awad,M. M.; Denning,W. L.; Diao,L.; Wang,J.; Parra-Cuentas,E. R.; Wistuba,I. I.; Soucheray,M.; Thai,T.; Asahina,H.; Kitajima,S.; Altabef,A.; Cavanaugh,J. D.; Rhee,K.; Gao,P.; Zhang,H.; Fecci,P. E.; Shimamura,T.; Hellmann,M. D.; Heymach,J. V.; Hodi,F. S.; Freeman,G. J.; Barbie,D. A.; Dranoff,G.; Hammerman,P. S.; Wong,K. K. STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment Cancer research 2016 ;76(5):999-1008
  • Arteaga,M.; Shang,N.; Ding,X.; Yong,S.; Cotler,S. J.; Denning,M. F.; Shimamura,T.; Breslin,P.; Luscher,B.; Qiu,W. Inhibition of SIRT2 suppresses hepatic fibrosis American journal of physiology.Gastrointestinal and liver physiology 2016 ;310(11):G1155-68
  • Soucheray,M.; Capelletti,M.; Pulido,I.; Kuang,Y.; Paweletz,C. P.; Becker,J. H.; Kikuchi,E.; Xu,C.; Patel,T. B.; Al-Shahrour,F.; Carretero,J.; Wong,K. K.; Janne,P. A.; Shapiro,G. I.; Shimamura,T. Intratumoral heterogeneity in EGFR mutant NSCLC results in divergent resistance mechanisms in response to EGFR tyrosine kinase inhibition Cancer research 2015 ;75(20):4372-4383
  • Christensen,C. L.; Kwiatkowski,N.; Abraham,B. J.; Carretero,J.; Al-Shahrour,F.; Zhang,T.; Chipumuro,E.; Herter-Sprie,G. S.; Akbay,E. A.; Altabef,A.; Zhang,J.; Shimamura,T.; Capelletti,M.; Reibel,J. B.; Cavanaugh,J. D.; Gao,P.; Liu,Y.; Michaelsen,S. R.; Poulsen,H. S.; Aref,A. R.; Barbie,D. A.; Bradner,J. E.; George,R. E.; Gray,N. S.; Young,R. A.; Wong,K. K. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor CANCER CELL 2014 ;26(6):909-922
  • Hanna,S. C.; Krishnan,B.; Bailey,S. T.; Moschos,S. J.; Kuan,P. F.; Shimamura,T.; Osborne,L. D.; Siegel,M. B.; Duncan,L. M.; O'Brien,E. T.,3rd; Superfine,R.; Miller,C. R.; Simon,M. C.; Wong,K. K.; Kim,W. Y. HIF1alpha and HIF2alpha independently activate SRC to promote melanoma metastases The Journal of clinical investigation 2013 ;123(5):2078-2093
  • Shimamura,T.; Chen,Z.; Soucheray,M.; Carretero,J.; Kikuchi,E.; Tchaicha,J. H.; Gao,Y.; Cheng,K. A.; Cohoon,T. J.; Qi,J.; Akbay,E.; Kimmelman,A. C.; Kung,A. L.; Bradner,J. E.; Wong,K. K. Efficacy of BET bromodomain inhibition in Kras-mutant non-small cell lung cancer Clinical cancer research : an official journal of the American Association for Cancer Research 2013 ;19(22):6183-6192
  • Cortot,A. B.; Repellin,C. E.; Shimamura,T.; Capelletti,M.; Zejnullahu,K.; Ercan,D.; Christensen,J. G.; Wong,K. K.; Gray,N. S.; Janne,P. A.Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway Cancer research 2013 ;73(2):834-843
  • Akbay,E. A.; Koyama,S.; Carretero,J.; Altabef,A.; Tchaicha,J. H.; Christensen,C. L.; Mikse,O. R.; Cherniack,A. D.; Beauchamp,E. M.; Pugh,T. J.; Wilkerson,M. D.; Fecci,P. E.; Butaney,M.; Reibel,J. B.; Soucheray,M.; Cohoon,T. J.; Janne,P. A.; Meyerson,M.; Hayes,D. N.; Shapiro,G. I.; Shimamura,T.; Sholl,L. M.; Rodig,S. J.; Freeman,G. J.; Hammerman,P. S.; Dranoff,G.; Wong,K. K.Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors Cancer discovery 2013 ;3(12):1355-1363
  • Xu,L.; Kikuchi,E.; Xu,C.; Ebi,H.; Ercan,D.; Cheng,K. A.; Padera,R.; Engelman,J. A.; Janne,P. A.; Shapiro,G. I.; Shimamura,T.; Wong,K. K.Combined EGFR/MET or EGFR/HSP90 inhibition is effective in the treatment of lung cancers codriven by mutant EGFR containing T790M and MET Cancer research 2012 ;72(13):3302-3311
  • Straume,O.; Shimamura,T.; Lampa,M. J.; Carretero,J.; Oyan,A. M.; Jia,D.; Borgman,C. L.; Soucheray,M.; Downing,S. R.; Short,S. M.; Kang,S. Y.; Wang,S.; Chen,L.; Collett,K.; Bachmann,I.; Wong,K. K.; Shapiro,G. I.; Kalland,K. H.; Folkman,J.; Watnick,R. S.; Akslen,L. A.; Naumov,G. N.Suppression of heat shock protein 27 induces long-term dormancy in human breast cancer Proceedings of the National Academy of Sciences of the United States of America 2012 ;109(22):8699-8704
  • Ercan,D.; Xu,C.; Yanagita,M.; Monast,C. S.; Pratilas,C. A.; Montero,J.; Butaney,M.; Shimamura,T.; Sholl,L.; Ivanova,E. V.; Tadi,M.; Rogers,A.; Repellin,C.; Capelletti,M.; Maertens,O.; Goetz,E. M.; Letai,A.; Garraway,L. A.; Lazzara,M. J.; Rosen,N.; Gray,N. S.; Wong,K. K.; Janne,P. A.Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors Cancer discovery 2012 ;2(10):934-947
  • Shimamura,T.; Jeng,D.; Lucas,A.; Essani,K.Suppression of neointimal hyperplasia following angioplasty-induced vascular injury in pigs infected with swinepox virus The open virology journal 2012 ;6:91-96
  • Shimamura,T.; Perera,S. A.; Foley,K. P.; Sang,J.; Rodig,S. J.; Inoue,T.; Chen,L.; Li,D.; Carretero,J.; Li,Y. C.; Sinha,P.; Carey,C. D.; Borgman,C. L.; Jimenez,J. P.; Meyerson,M.; Ying,W.; Barsoum,J.; Wong,K. K.; Shapiro,G. I.Ganetespib (STA-9090), a nongeldanamycin HSP90 inhibitor, has potent antitumor activity in in vitro and in vivo models of non-small cell lung cancer Clinical cancer research : an official journal of the American Association for Cancer Research 2012 ;18(18):4973-4985
  • Chen,Z.; Cheng,K.; Walton,Z.; Wang,Y.; Ebi,H.; Shimamura,T.; Liu,Y.; Tupper,T.; Ouyang,J.; Li,J.; Gao,P.; Woo,M. S.; Xu,C.; Yanagita,M.; Altabef,A.; Wang,S.; Lee,C.; Nakada,Y.; Pena,C. G.; Sun,Y.; Franchetti,Y.; Yao,C.; Saur,A.; Cameron,M. D.; Nishino,M.; Hayes,D. N.; Wilkerson,M. D.; Roberts,P. J.; Lee,C. B.; Bardeesy,N.; Butaney,M.; Chirieac,L. R.; Costa,D. B.; Jackman,D.; Sharpless,N. E.; Castrillon,D. H.; Demetri,G. D.; Janne,P. A.; Pandolfi,P. P.; Cantley,L. C.; Kung,A. L.; Engelman,J. A.; Wong,K. K.A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response Nature 2012 ;483(7391):613-617
  • Liu,W.; Monahan,K. B.; Pfefferle,A. D.; Shimamura,T.; Sorrentino,J.; Chan,K. T.; Roadcap,D. W.; Ollila,D. W.; Thomas,N. E.; Castrillon,D. H.; Miller,C. R.; Perou,C. M.; Wong,K. K.; Bear,J. E.; Sharpless,N. E.LKB1/STK11 inactivation leads to expansion of a prometastatic tumor subpopulation in melanoma CANCER CELL 2012 ;21(6):751-764
  • Sasaki,T.; Koivunen,J.; Ogino,A.; Yanagita,M.; Nikiforow,S.; Zheng,W.; Lathan,C.; Marcoux,J. P.; Du,J.; Okuda,K.; Capelletti,M.; Shimamura,T.; Ercan,D.; Stumpfova,M.; Xiao,Y.; Weremowicz,S.; Butaney,M.; Heon,S.; Wilner,K.; Christensen,J. G.; Eck,M. J.; Wong,K. K.; Lindeman,N.; Gray,N. S.; Rodig,S. J.; Janne,P. A.A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors Cancer research 2011 ;71(18):6051-6060
  • Raina,D.; Kosugi,M.; Ahmad,R.; Panchamoorthy,G.; Rajabi,H.; Alam,M.; Shimamura,T.; Shapiro,G. I.; Supko,J.; Kharbanda,S.; Kufe,D.Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells Molecular Cancer Therapeutics 2011 ;10(5):806-816
  • Will,B.; Siddiqi,T.; Jorda,M. A.; Shimamura,T.; Luptakova,K.; Staber,P. B.; Costa,D. B.; Steidl,U.; Tenen,D. G.; Kobayashi,S.Apoptosis induced by JAK2 inhibition is mediated by Bim and enhanced by the BH3 mimetic ABT-737 in JAK2 mutant human erythroid cells Blood 2010 ;115(14):2901-2909
  • Liang,M. C.; Ma,J.; Chen,L.; Kozlowski,P.; Qin,W.; Li,D.; Goto,J.; Shimamura,T.; Hayes,D. N.; Meyerson,M.; Kwiatkowski,D. J.; Wong,K. K.TSC1 loss synergizes with KRAS activation in lung cancer development in the mouse and confers rapamycin sensitivity Oncogene 2010 ;29(11):1588-1597
  • Carretero,J.; Shimamura,T.; Rikova,K.; Jackson,A. L.; Wilkerson,M. D.; Borgman,C. L.; Buttarazzi,M. S.; Sanofsky,B. A.; McNamara,K. L.; Brandstetter,K. A.; Walton,Z. E.; Gu,T. L.; Silva,J. C.; Crosby,K.; Shapiro,G. I.; Maira,S. M.; Ji,H.; Castrillon,D. H.; Kim,C. F.; Garcia-Echeverria,C.; Bardeesy,N.; Sharpless,N. E.; Hayes,N. D.; Kim,W. Y.; Engelman,J. A.; Wong,K. K.Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors CANCER CELL 2010 ;17(6):547-559
  • Chen,Z.; Sasaki,T.; Tan,X.; Carretero,J.; Shimamura,T.; Li,D.; Xu,C.; Wang,Y.; Adelmant,G. O.; Capelletti,M.; Lee,H. J.; Rodig,S. J.; Borgman,C.; Park,S. I.; Kim,H. R.; Padera,R.; Marto,J. A.; Gray,N. S.; Kung,A. L.; Shapiro,G. I.; Janne,P. A.; Wong,K. K.Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene Cancer research 2010 ;70(23):9827-9836
  • Sos,M. L.; Michel,K.; Zander,T.; Weiss,J.; Frommolt,P.; Peifer,M.; Li,D.; Ullrich,R.; Koker,M.; Fischer,F.; Shimamura,T.; Rauh,D.; Mermel,C.; Fischer,S.; Stuckrath,I.; Heynck,S.; Beroukhim,R.; Lin,W.; Winckler,W.; Shah,K.; LaFramboise,T.; Moriarty,W. F.; Hanna,M.; Tolosi,L.; Rahnenfuhrer,J.; Verhaak,R.; Chiang,D.; Getz,G.; Hellmich,M.; Wolf,J.; Girard,L.; Peyton,M.; Weir,B. A.; Chen,T. H.; Greulich,H.; Barretina,J.; Shapiro,G. I.; Garraway,L. A.; Gazdar,A. F.; Minna,J. D.; Meyerson,M.; Wong,K. K.; Thomas,R. K.Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions The Journal of clinical investigation 2009 ;119(6):1727-1740
  • Wingo,S. N.; Gallardo,T. D.; Akbay,E. A.; Liang,M. C.; Contreras,C. M.; Boren,T.; Shimamura,T.; Miller,D. S.; Sharpless,N. E.; Bardeesy,N.; Kwiatkowski,D. J.; Schorge,J. O.; Wong,K. K.; Castrillon,D. H.Somatic LKB1 mutations promote cervical cancer progression PLoS ONE 2009 ;4(4):e5137
  • Perera,S. A.; Li,D.; Shimamura,T.; Raso,M. G.; Ji,H.; Chen,L.; Borgman,C. L.; Zaghlul,S.; Brandstetter,K. A.; Kubo,S.; Takahashi,M.; Chirieac,L. R.; Padera,R. F.; Bronson,R. T.; Shapiro,G. I.; Greulich,H.; Meyerson,M.; Guertler,U.; Chesa,P. G.; Solca,F.; Wistuba,I. I.; Wong,K. K.HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy Proceedings of the National Academy of Sciences of the United States of America 2009 ;106(2):474-479
  • Ullrich,R. T.; Zander,T.; Neumaier,B.; Koker,M.; Shimamura,T.; Waerzeggers,Y.; Borgman,C. L.; Tawadros,S.; Li,H.; Sos,M. L.; Backes,H.; Shapiro,G. I.; Wolf,J.; Jacobs,A. H.; Thomas,R. K.; Winkeler,A.Early detection of erlotinib treatment response in NSCLC by 3'-deoxy-3'-[F]-fluoro-L-thymidine ([F]FLT) positron emission tomography (PET) PLoS ONE 2008 ;3(12):e3908
  • Shimamura,T.; Shapiro,G. I.Heat shock protein 90 inhibition in lung cancer Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2008 ;3(6 Suppl 2):S152-9
  • Shimamura,T.; Li,D.; Ji,H.; Haringsma,H. J.; Liniker,E.; Borgman,C. L.; Lowell,A. M.; Minami,Y.; McNamara,K.; Perera,S. A.; Zaghlul,S.; Thomas,R. K.; Greulich,H.; Kobayashi,S.; Chirieac,L. R.; Padera,R. F.; Kubo,S.; Takahashi,M.; Tenen,D. G.; Meyerson,M.; Wong,K. K.; Shapiro,G. I.Hsp90 inhibition suppresses mutant EGFR-T790M signaling and overcomes kinase inhibitor resistance Cancer research 2008 ;68(14):5827-5838
  • Li,D.; Ambrogio,L.; Shimamura,T.; Kubo,S.; Takahashi,M.; Chirieac,L. R.; Padera,R. F.; Shapiro,G. I.; Baum,A.; Himmelsbach,F.; Rettig,W. J.; Meyerson,M.; Solca,F.; Greulich,H.; Wong,K. K.BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models Oncogene 2008 ;27(34):4702-4711
  • Smith,D.; Shimamura,T.; Barbera,S.; Bejcek,B. E.NF-kappaB controls growth of glioblastomas/astrocytomas MOLECULAR AND CELLULAR BIOCHEMISTRY 2008 ;307(1-2):141-147
  • Deng,J.; Shimamura,T.; Perera,S.; Carlson,N. E.; Cai,D.; Shapiro,G. I.; Wong,K. K.; Letai,A.Proapoptotic BH3-only BCL-2 family protein BIM connects death signaling from epidermal growth factor receptor inhibition to the mitochondrion Cancer research 2007 ;67(24):11867-11875
  • Yuza,Y.; Glatt,K. A.; Jiang,J.; Greulich,H.; Minami,Y.; Woo,M. S.; Shimamura,T.; Shapiro,G.; Lee,J. C.; Ji,H.; Feng,W.; Chen,T. H.; Yanagisawa,H.; Wong,K. K.; Meyerson,M.Allele-dependent variation in the relative cellular potency of distinct EGFR inhibitors Cancer Biology & Therapy 2007 ;6(5):661-667
  • Engelman,J. A.; Zejnullahu,K.; Gale,C. M.; Lifshits,E.; Gonzales,A. J.; Shimamura,T.; Zhao,F.; Vincent,P. W.; Naumov,G. N.; Bradner,J. E.; Althaus,I. W.; Gandhi,L.; Shapiro,G. I.; Nelson,J. M.; Heymach,J. V.; Meyerson,M.; Wong,K. K.; Janne,P. A.PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib Cancer research 2007 ;67(24):11924-11932
  • Li,D.; Ji,H.; Zaghlul,S.; McNamara,K.; Liang,M. C.; Shimamura,T.; Kubo,S.; Takahashi,M.; Chirieac,L. R.; Padera,R. F.; Scott,A. M.; Jungbluth,A. A.; Cavenee,W. K.; Old,L. J.; Demetri,G. D.; Wong,K. K.Therapeutic anti-EGFR antibody 806 generates responses in murine de novo EGFR mutant-dependent lung carcinomas The Journal of clinical investigation 2007 ;117(2):346-352
  • Li,D.; Shimamura,T.; Ji,H.; Chen,L.; Haringsma,H. J.; McNamara,K.; Liang,M. C.; Perera,S. A.; Zaghlul,S.; Borgman,C. L.; Kubo,S.; Takahashi,M.; Sun,Y.; Chirieac,L. R.; Padera,R. F.; Lindeman,N. I.; Janne,P. A.; Thomas,R. K.; Meyerson,M. L.; Eck,M. J.; Engelman,J. A.; Shapiro,G. I.; Wong,K. K.Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy CANCER CELL 2007 ;12(1):81-93
  • Ji,H.; Ramsey,M. R.; Hayes,D. N.; Fan,C.; McNamara,K.; Kozlowski,P.; Torrice,C.; Wu,M. C.; Shimamura,T.; Perera,S. A.; Liang,M. C.; Cai,D.; Naumov,G. N.; Bao,L.; Contreras,C. M.; Li,D.; Chen,L.; Krishnamurthy,J.; Koivunen,J.; Chirieac,L. R.; Padera,R. F.; Bronson,R. T.; Lindeman,N. I.; Christiani,D. C.; Lin,X.; Shapiro,G. I.; Janne,P. A.; Johnson,B. E.; Meyerson,M.; Kwiatkowski,D. J.; Castrillon,D. H.; Bardeesy,N.; Sharpless,N. E.; Wong,K. K.LKB1 modulates lung cancer differentiation and metastasis Nature 2007 ;448(7155):807-810
  • Minami,Y.; Shimamura,T.; Shah,K.; LaFramboise,T.; Glatt,K. A.; Liniker,E.; Borgman,C. L.; Haringsma,H. J.; Feng,W.; Weir,B. A.; Lowell,A. M.; Lee,J. C.; Wolf,J.; Shapiro,G. I.; Wong,K. K.; Meyerson,M.; Thomas,R. K.The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor HKI-272 Oncogene 2007 ;26(34):5023-5027
  • Kobayashi,S.; Shimamura,T.; Monti,S.; Steidl,U.; Hetherington,C. J.; Lowell,A. M.; Golub,T.; Meyerson,M.; Tenen,D. G.; Shapiro,G. I.; Halmos,B.Transcriptional profiling identifies cyclin D1 as a critical downstream effector of mutant epidermal growth factor receptor signaling Cancer research 2006 ;66(23):11389-11398
  • Shimamura,T.; Ji,H.; Minami,Y.; Thomas,R. K.; Lowell,A. M.; Shah,K.; Greulich,H.; Glatt,K. A.; Meyerson,M.; Shapiro,G. I.; Wong,K. K.Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal growth factor receptor and ERBB2 inhibitor HKI-272 Cancer research 2006 ;66(13):6487-6491
  • Ji,H.; Li,D.; Chen,L.; Shimamura,T.; Kobayashi,S.; McNamara,K.; Mahmood,U.; Mitchell,A.; Sun,Y.; Al-Hashem,R.; Chirieac,L. R.; Padera,R.; Bronson,R. T.; Kim,W.; Janne,P. A.; Shapiro,G. I.; Tenen,D.; Johnson,B. E.; Weissleder,R.; Sharpless,N. E.; Wong,K. K.The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies CANCER CELL 2006 ;9(6):485-495