A framework for identification of actionable cancer genome dependencies in small cell lung cancer

作者：Sos Martin L^*; Dietlein Felix; Peifer Martin; Schoettle Jakob; Balke Want Hyatt; Mueller Christian; Koker Mirjam; Richters Andre; Heynck Stefanie; Malchers Florian; Heuckmann Johannes M; Seidel Danila; Eyers Patrick A; Ullrich Roland T; Antonchick Andrey P; Vintonyak Viktor V; Schneider Peter M; Ninomiya Takashi; Waldmann Herbert; Buettner Reinhard; Rauh Daniel; Heukamp Lukas C; Thomas Roman K

来源：Proceedings of the National Academy of Sciences, 2012, 109(42): 17034-17039.

DOI：10.1073/pnas.1207310109

Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. The prognosis of SCLC patients is devastating and no biologically targeted therapeutics are active in this tumor type. To develop a framework for development of specific SCLC-targeted drugs we conducted a combined genomic and pharmacological vulnerability screen in SCLC cell lines. We show that SCLC cell lines capture the genomic landscape of primary SCLC tumors and provide genetic predictors for activity of clinically relevant inhibitors by screening 267 compounds across 44 of these cell lines. We show Aurora kinase inhibitors are effective in SCLC cell lines bearing MYC amplification, which occur in 3-7% of SCLC patients. In MYC-amplified SCLC cells Aurora kinase inhibition associates with G2/M-arrest, inactivation of PI3-kinase (PI3K) signaling, and induction of apoptosis. Aurora dependency in SCLC primarily involved Aurora B, required its kinase activity, and was independent of depletion of cytoplasmic levels of MYC. Our study suggests that a fraction of SCLC patients may benefit from therapeutic inhibition of Aurora B. Thus, thorough chemical and genomic exploration of SCLC cell lines may provide starting points for further development of rational targeted therapeutic intervention in this deadly tumor type.

• 出版日期2012-10-16