XSystematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer

Hyun Seok Kim, Saurabh Mendiratta, Jiyeon Kim, Chad Victor Pecot, Jill E. Larsen, Iryna Zubovych, Bo Yeun Seo, Jimi Kim, Banu Eskiocak, Hannah Chung, Elizabeth McMillan, Sherry Wu, Jef De Brabander, Kakajan Komurov, Jason E. Toombs, Shuguang Wei, Michael Peyton, Noelle Williams, Adi F. Gazdar, Bruce A. PosnerRolf A. Brekken, Anil K. Sood, Ralph J. Deberardinis, Michael G. Roth, John D. Minna, Michael A. White

Research output: Contribution to journalArticle

108 Scopus citations

Abstract

Context-specific molecular vulnerabilities that arise during tumor evolution represent an attractive intervention target class. However, the frequency and diversity of somatic lesions detected among lung tumors can confound efforts to identify these targets. To confront this challenge, we have applied parallel screening of chemical and genetic perturbations within a panel of molecularly annotated NSCLC lines to identify intervention opportunities tightly linked to molecular response indicators predictive of target sensitivity. Anchoring this analysis on a matched tumor/normal cell model from a lung adenocarcinoma patient identified three distinct target/response-indicator pairings that are represented with significant frequencies (6%-16%) in the patient population. These include NLRP3 mutation/inflammasome activation-dependent FLIP addiction, co-occurring KRAS and LKB1 mutation-driven COPI addiction, and selective sensitivity to a synthetic indolotriazine that is specified by a seven-gene expression signature. Target efficacies were validated in vivo, and mechanism-of-action studies informed generalizable principles underpinning cancer cell biology.

Original languageEnglish (US)
Number of pages1
JournalCell
Volume155
Issue number3
DOIs
StatePublished - Oct 24 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Kim, H. S., Mendiratta, S., Kim, J., Pecot, C. V., Larsen, J. E., Zubovych, I., Seo, B. Y., Kim, J., Eskiocak, B., Chung, H., McMillan, E., Wu, S., De Brabander, J., Komurov, K., Toombs, J. E., Wei, S., Peyton, M., Williams, N., Gazdar, A. F., ... White, M. A. (2013). XSystematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer. Cell, 155(3). https://doi.org/10.1016/j.cell.2013.09.041