Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions

Martin L. Sos, Kathrin Michel, Thomas Zander, Jonathan Weiss, Peter Frommolt, Martin Peifer, Danan Li, Roland Ullrich, Mirjam Koker, Florian Fischer, Takeshi Shimamura, Daniel Rauh, Craig Mermel, Stefanie Fischer, Isabel Stückrath, Stefanie Heynck, Rameen Beroukhim, William Lin, Wendy Winckler, Kinjal ShahThomas LaFramboise, Whei F. Moriarty, Megan Hanna, Laura Tolosi, Jörg Rahnenführer, Roel Verhaak, Derek Chiang, Gad Getz, Martin Hellmich, Jürgen Wolf, Luc Girard, Michael Peyton, Barbara A. Weir, Tzu Hsiu Chen, Heidi Greulich, Jordi Barretina, Geoffrey I. Shapiro, Levi A. Garraway, Adi F. Gazdar, John D. Minna, Matthew Meyerson, Kwok Kin Wong, Roman K. Thomas

Research output: Contribution to journalArticle

199 Citations (Scopus)

Abstract

Somatic genetic alterations in cancers have been linked with response to targeted therapeutics by creation of specific dependency on activated oncogenic signaling pathways. However, no tools currently exist to systematically connect such genetic lesions to therapeutic vulnerability. We have therefore developed a genomics approach to identify lesions associated with therapeutically relevant oncogene dependency. Using integrated genomic profiling, we have demonstrated that the genomes of a large panel of human non-small cell lung cancer (NSCLC) cell lines are highly representative of those of primary NSCLC tumors. Using cell-based compound screening coupled with diverse computational approaches to integrate orthogonal genomic and biochemical data sets, we identified molecular and genomic predictors of therapeutic response to clinically relevant compounds. Using this approach, we showed that v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations confer enhanced Hsp90 dependency and validated this finding in mice with KRAS-driven lung adenocarcinoma, as these mice exhibited dramatic tumor regression when treated with an Hsp90 inhibitor. In addition, we found that cells with copy number enhancement of v-abl Abelson murine leukemia viral oncogene homolog 2 (ABL2) and ephrin receptor kinase and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) (SRC) kinase family genes were exquisitely sensitive to treatment with the SRC/ABL inhibitor dasatinib, both in vitro and when it xenografted into mice. Thus, genomically annotated cell-line collections may help translate cancer genomics information into clinical practice by defining critical pathway dependencies amenable to therapeutic inhibition.

Original languageEnglish (US)
Pages (from-to)1727-1740
Number of pages14
JournalJournal of Clinical Investigation
Volume119
Issue number6
DOIs
StatePublished - Jun 1 2009

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Oncogenes
Non-Small Cell Lung Carcinoma
Genomics
Sarcoma
Pharmaceutical Preparations
Neoplasms
Eph Family Receptors
Cell Line
Critical Pathways
src-Family Kinases
Therapeutics
varespladib methyl
Leukemia
Phosphotransferases
Genome
Mutation
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Sos, M. L., Michel, K., Zander, T., Weiss, J., Frommolt, P., Peifer, M., ... Thomas, R. K. (2009). Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions. Journal of Clinical Investigation, 119(6), 1727-1740. https://doi.org/10.1172/JCI37127

Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions. / Sos, Martin L.; Michel, Kathrin; Zander, Thomas; Weiss, Jonathan; Frommolt, Peter; Peifer, Martin; Li, Danan; Ullrich, Roland; Koker, Mirjam; Fischer, Florian; Shimamura, Takeshi; Rauh, Daniel; Mermel, Craig; Fischer, Stefanie; Stückrath, Isabel; Heynck, Stefanie; Beroukhim, Rameen; Lin, William; Winckler, Wendy; Shah, Kinjal; LaFramboise, Thomas; Moriarty, Whei F.; Hanna, Megan; Tolosi, Laura; Rahnenführer, Jörg; Verhaak, Roel; Chiang, Derek; Getz, Gad; Hellmich, Martin; Wolf, Jürgen; Girard, Luc; Peyton, Michael; Weir, Barbara A.; Chen, Tzu Hsiu; Greulich, Heidi; Barretina, Jordi; Shapiro, Geoffrey I.; Garraway, Levi A.; Gazdar, Adi F.; Minna, John D.; Meyerson, Matthew; Wong, Kwok Kin; Thomas, Roman K.

In: Journal of Clinical Investigation, Vol. 119, No. 6, 01.06.2009, p. 1727-1740.

Research output: Contribution to journalArticle

Sos, ML, 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, Stückrath, I, Heynck, S, Beroukhim, R, Lin, W, Winckler, W, Shah, K, LaFramboise, T, Moriarty, WF, Hanna, M, Tolosi, L, Rahnenführer, J, Verhaak, R, Chiang, D, Getz, G, Hellmich, M, Wolf, J, Girard, L, Peyton, M, Weir, BA, Chen, TH, Greulich, H, Barretina, J, Shapiro, GI, Garraway, LA, Gazdar, AF, Minna, JD, Meyerson, M, Wong, KK & Thomas, RK 2009, 'Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions', Journal of Clinical Investigation, vol. 119, no. 6, pp. 1727-1740. https://doi.org/10.1172/JCI37127
Sos, Martin L. ; Michel, Kathrin ; Zander, Thomas ; Weiss, Jonathan ; Frommolt, Peter ; Peifer, Martin ; Li, Danan ; Ullrich, Roland ; Koker, Mirjam ; Fischer, Florian ; Shimamura, Takeshi ; Rauh, Daniel ; Mermel, Craig ; Fischer, Stefanie ; Stückrath, Isabel ; Heynck, Stefanie ; Beroukhim, Rameen ; Lin, William ; Winckler, Wendy ; Shah, Kinjal ; LaFramboise, Thomas ; Moriarty, Whei F. ; Hanna, Megan ; Tolosi, Laura ; Rahnenführer, Jörg ; Verhaak, Roel ; Chiang, Derek ; Getz, Gad ; Hellmich, Martin ; Wolf, Jürgen ; Girard, Luc ; Peyton, Michael ; Weir, Barbara A. ; Chen, Tzu Hsiu ; Greulich, Heidi ; Barretina, Jordi ; Shapiro, Geoffrey I. ; Garraway, Levi A. ; Gazdar, Adi F. ; Minna, John D. ; Meyerson, Matthew ; Wong, Kwok Kin ; Thomas, Roman K. / Predicting drug susceptibility of non-small cell lung cancers based on genetic lesions. In: Journal of Clinical Investigation. 2009 ; Vol. 119, No. 6. pp. 1727-1740.
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AU - Peifer, Martin

AU - Li, Danan

AU - Ullrich, Roland

AU - Koker, Mirjam

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AU - Hellmich, Martin

AU - Wolf, Jürgen

AU - Girard, Luc

AU - Peyton, Michael

AU - Weir, Barbara A.

AU - Chen, Tzu Hsiu

AU - Greulich, Heidi

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AU - Shapiro, Geoffrey I.

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AU - Gazdar, Adi F.

AU - Minna, John D.

AU - Meyerson, Matthew

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