细胞期刊(Cell)2013-10-28 8:38 PM

Systematic Identification of Molecular Subtype-Selective Vulnerabilities in Non-Small-Cell Lung Cancer

Highlights
- 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
Summary
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.

KEYWORDS

SHARE & LIKE

COMMENTS

ABOUT THE AUTHOR

细胞期刊(Cell)

0 Following 3 Fans 0 Projects 125 Articles

SIMILAR ARTICLES

Epigenetic mechanisms have been proposed to play crucial roles in mammalian development, but their precise functions are only partially understood. To

Read More

Summary Replenishing insulin-producing pancreatic β cell mass will benefit both type I and type II diabetics. In adults, pancreatic β cells are gene

Read More

Summary Replenishing insulin-producing pancreatic β cell mass will benefit both type I and type II diabetics. In adults, pancreatic β cells are gene

Read More

Summary 5-methylcytosine is a major epigenetic modification that is sometimes called “the fifth nucleotide.” However, our knowledge of how offspring

Read More

Summary 5-methylcytosine is a major epigenetic modification that is sometimes called “the fifth nucleotide.” However, our knowledge of how offspring

Read More

Summary All metazoan guts are subjected to immunologically unique conditions in which an efficient antimicrobial system operates to eliminate pathog

Read More

Summary All metazoan guts are subjected to immunologically unique conditions in which an efficient antimicrobial system operates to eliminate pathog

Read More

Summary Alterations of symbiosis between microbiota and intestinal epithelial cells (IEC) are associated with intestinal and systemic pathologies. I

Read More

Summary Alterations of symbiosis between microbiota and intestinal epithelial cells (IEC) are associated with intestinal and systemic pathologies. I

Read More

Summary The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify

Read More