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

Micrograph of squamous carcinoma, a type of non-small-cell lung cancer

Micrograph of squamous carcinoma, a type of non-small-cell lung cancer (from Wikimedia Commons)

Kim HS, Mendiratta S, Kim J, Pecot CV, Larsen JE, Zubovych IO, Seo BY, Kim J, Eskiocak B, Chung H, McMillan E, Wu S, De Brabander JK, Komurov K, Wei S, Posner BA, Williams N, Brekken R, Sood AK, Deberardinis RJ, Roth MG, Minna JD, and White MA

Cell

October 24, 2013

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.

Program:
CTD²
Last updated: June 29, 2020