Author/Authors :
Hyun-Seok Kim، نويسنده , , Saurabh Mendiratta، نويسنده , , Jiyeon Kim، نويسنده , , Chad Victor Pecot، نويسنده , , Jill E. Larsen، نويسنده , , Iryna Zubovych، نويسنده , , Bo Yeun Seo، نويسنده , , Jimi Kim، نويسنده , , Banu Eskiocak، نويسنده , , Hannah Chung، نويسنده , , Elizabeth McMillan، نويسنده , , Sherry Wu، نويسنده , , Jef De Brabander، نويسنده , , Kakajan Komurov، نويسنده , , Jason E. Toombs، نويسنده , , Shuguang Wei، نويسنده , , Michael Peyton، نويسنده , , Noelle Williams، نويسنده , , Adi F. Gazdar، نويسنده , , Bruce A. Posner، نويسنده , , et al.، نويسنده ,
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.
