2. Academic Validation
  3. Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer

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

  • Cell. 2013 Oct 24;155(3):552-66. doi: 10.1016/j.cell.2013.09.041.
Hyun Seok Kim 1,  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 Posner,  Rolf A Brekken,  Anil K Sood,  Ralph J Deberardinis,  Michael G Roth,  John D Minna,  Michael A White
Affiliations

Affiliation

  • 1 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
PMID: 24243015 DOI: 10.1016/j.cell.2013.09.041
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.

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