Systematic Identification of Molecular Subtype-Selective Vulnerabilities in Non-Small-Cell Lung Cancer
Menée sur des lignées cellulaires de cancer du poumon non à petites cellules, puis validée in vivo, cette étude identifie des indicateurs moléculaires susceptibles de prédire la sensibilité à un agent thérapeutique
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.
"Systematic isolation of context-dependent vulnerabilities in NSCLC
"NLRP3 mutations drive addiction to FLIP expression
"Lysosome maturation is a metabolic bottleneck for KRAS/LKB1 tumors
"Selective sensitivity to an indolotriazine discriminates a NSCLC expression subtype
Parallel screening of chemical and RNAi libraries within a lung cancer patient s tumor and normal cells is employed for identification of intervention targets. Analysis of tumor cell-selective target activity within a large population of molecularly annotated lung cancer cell lines identified molecular-response indicators predictive of target sensitivity.
Cell , résumé, 2012