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

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.

Pathogenesis of hepatocellular carcinoma and molecular therapies.

PURPOSE OF REVIEW: Over the past decades, advances in the knowledge of the molecular pathogenesis of hepatocellular carcinoma (HCC) have allowed significant improvements in the therapeutic management of this devastating disease. Several investigations have established the role of aberrant activation of major intracellular signaling pathways during human hepatocarcinogenesis. Genome-wide analysis of DNA copy number changes and gene expression led to the identification of gene signatures and novel targets for cancer treatment. Numerous attempts have tried to develop a molecular classification of HCC. This review aims to summarize the most relevant genetic alterations and pathways involved in the development and progression of HCC, providing an overview of the molecular targeted therapies tested so far in human HCC. RECENT FINDINGS: The discovery of sorafenib, a multikinase inhibitor, as a treatment with survival benefits in patients with advanced HCC, has become a major breakthrough in the clinical management of HCC. For the first time, a molecular therapy was able to demonstrate significant efficacy for the treatment of HCC patients. New guidelines have established the ideal endpoints for the design of clinical trials for HCC. At last, a molecular classification of HCC based on genome-wide investigations, able to identify patient subclasses according to drug sensitivity will lead to a more personalized medicine. SUMMARY: In this review, we provide a comprehensive analysis of the underlying molecular mechanisms leading to human hepatocarcinogenesis, providing the scientific rationale for the development of new therapeutic targets.