Article

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

Max Planck Institute for Neurological Research, Klaus-Joachim-Zülch Laboratories of Max Planck Society, and University of Köln Medical Faculty, University of Köln, Cologne, Germany.
The Journal of clinical investigation (impact factor: 15.39). 06/2009; 119(6):1727-40. DOI:10.1172/JCI37127 pp.1727-40
Source: PubMed

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.

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Keywords

cancer genomics information
 
clinically relevant compounds
 
copy number enhancement
 
defining critical pathway dependencies amenable
 
genomic predictors
 
genomic profiling
 
genomically annotated cell-line collections
 
genomics approach
 
KRAS-driven lung adenocarcinoma
 
large panel
 
mice exhibited dramatic tumor regression
 
orthogonal genomic
 
primary NSCLC tumors
 
Schmidt-Ruppin A-2
 
Somatic genetic alterations
 
SRC/ABL inhibitor dasatinib
 
therapeutic inhibition
 
therapeutically relevant oncogene dependency
 
v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
 
v-src sarcoma
 

Martin L Sos