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

Authors :
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
Source :
The Journal of clinical investigation [J Clin Invest] 2009 Jun; Vol. 119 (6), pp. 1727-40. Date of Electronic Publication: 2009 May 18.
Publication Year :
2009

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.

Details

Language :
English
ISSN :
1558-8238
Volume :
119
Issue :
6
Database :
MEDLINE
Journal :
The Journal of clinical investigation
Publication Type :
Academic Journal
Accession number :
19451690
Full Text :
https://doi.org/10.1172/JCI37127