Crebbp loss drives small cell lung cancer and increases sensitivity to HDAC inhibition
Menée in vitro et in vivo sur des modèles de cancer du poumon à petites cellules, cette étude met notamment en évidence des mécanismes par lesquels le gène CREBBP exerce une fonction de suppresseur de tumeurs
CREBBP, encoding an acetyltransferase, is among the most frequently mutated genes in small cell lung cancer (SCLC), a deadly neuroendocrine tumor type. We report acceleration of SCLC upon Crebbp inactivation in an autochthonous mouse model. Extending these observations beyond the lung, broad Crebbp deletion in mouse neuroendocrine cells cooperated with Rb1/Trp53 loss to promote neuroendocrine thyroid and pituitary carcinomas. Gene expression analyses showed that Crebbp loss results in reduced expression of tight junction and cell adhesion genes, including Cdh1, across neuroendocrine tumor types, while suppression of Cdh1 promoted transformation in SCLC. CDH1 and other adhesion genes exhibited reduced histone acetylation with Crebbp inactivation. Treatment with the histone deacetylase inhibitor Pracinostat increased histone acetylation and restored CDH1 expression. Additionally, a subset of Rb1/Trp53/Crebbp-deficient SCLC exhibited exceptional responses to Pracinostat in vivo. Thus, CREBBP acts as a potent tumor suppressor in SCLC and inactivation of CREBBP enhances responses to a targeted therapy.