TRP53 Mutants Drive Neuroendocrine Lung Cancer Through Loss-of-Function Mechanisms with Gain-of-Function Effects on Chemotherapy Response.

ABSTRACT: Lung cancer is the leading cause of cancer-related deaths with small-cell lung cancer (SCLC) as the most aggressive subtype. Preferential occurrence of TP53 missense mutations rather than loss implicates a selective advantage for TP53-mutant expression in SCLC pathogenesis. We show that lung epithelial expression of R270H and R172H (R273H and R175H in humans), common TRP53 mutants in lung cancer, combined with RB1 loss selectively results in two subtypes of neuroendocrine carcinoma, SCLC and large cell neuroendocrine carcinoma (LCNEC). Tumor initiation and progression occur in a remarkably consistent time frame with short latency and uniform progression to lethal metastatic disease by 7 months. R270H or R172H expression and TRP53 loss result in similar phenotypes demonstrating that TRP53 m

SUBMITTER: Akeno N 

PROVIDER: S-EPMC5716875 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature