@article{b2f69628a71d4e84bcec8f690aa984da,
title = "Crebbp loss drives small cell lung cancer and increases sensitivity to HDAC inhibition",
abstract = "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, whereas suppression of Cdh1 promoted transformation in SCLC. CDH1 and other adhesion genes exhibited reduced histone acetylation with Crebbp inactivation. Treatment with the histone deacetylase (HDAC) inhibitor Pracinostat increased histone acetylation and restored CDH1 expression. In addition, 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. SIGNIFICANCE: Our findings demonstrate that CREBBP loss in SCLC reduces histone acetylation and transcription of cellular adhesion genes, while driving tumorigenesis. These effects can be partially restored by HDAC inhibition, which exhibited enhanced effectiveness in Crebbp-deleted tumors. These data provide a rationale for selectively treating CREBBP-mutant SCLC with HDAC inhibitors.",
author = "Deshui Jia and Arnaud Augert and Kim, {Dong Wook} and Emily Eastwood and Nan Wu and Ibrahim, {Ali H.} and Kim, {Kee Beom} and Dunn, {Colin T.} and Pillai, {Smitha P.S.} and Gazdar, {Adi F.} and Hamid Bolouri and Park, {Kwon Sik} and David Macpherson",
note = "Funding Information: We thank Scott Dylla and Jorge Aguilar (AbbVie Stemcentrx) for providing the LU505 PDX model. We thank Ryan Basom and Qing Zhang, as well as the Fred Hutchinson Genomics and Bioinformatics Shared Resource for help with the generation and analysis of next-generation sequencing data, and Joe Hiatt for GSEA. We also acknowledge support from the Fred Hutchinson Histopathology and small-animal imaging Shared Resources, as well as the Research Histology Core and the Flow Cytometry Core at the UVA Medical Center. We are grateful to Valera Vasioukhin, Taran Gujral, Julien Sage, and Slobodan Beronja for critical reading of the manuscript. This work was supported by NIH (R01CA200547 to D. MacPherson; R01CA194461 and R03CA215777 to K.-S. Park), the American Cancer Society (RSG-15-066-01-TBG to K.-S. Park), and the David R. Jones Fund at University of Virginia (to K.-S. Park). D. Jia was supported by a postdoctoral fellowship from the International Association for the Study of Lung Cancer. E. Eastwood was supported by NIH training grant T32CA009657. This project was supported by NIH Support Grants for the FHCRC/UW Cancer Consortium Cancer Center (P30CA015704) and for the University of Virginia Cancer Center (P30CA044579). Funding Information: We thank Scott Dylla and Jorge Aguilar (AbbVie Stemcentrx) for providing the LU505 PDX model. We thank Ryan Basom and Qing Zhang, as well as the Fred Hutchinson Genomics and Bioinformat-ics Shared Resource for help with the generation and analysis of next-generation sequencing data, and Joe Hiatt for GSEA. We also acknowledge support from the Fred Hutchinson Histopathology and small-animal imaging Shared Resources, as well as the Research Histology Core and the Flow Cytometry Core at the UVA Medical Center. We are grateful to Valera Vasioukhin, Taran Gujral, Julien Sage, and Slobodan Beronja for critical reading of the manuscript. This work was supported by NIH (R01CA200547 to D. MacPher-son; R01CA194461 and R03CA215777 to K.-S. Park), the American Cancer Society (RSG-15-066-01-TBG to K.-S. Park), and the David R. Jones Fund at University of Virginia (to K.-S. Park). D. Jia was supported by a postdoctoral fellowship from the International Association for the Study of Lung Cancer. E. Eastwood was supported by NIH training grant T32CA009657. This project was supported by NIH Support Grants for the FHCRC/UW Cancer Consortium Cancer Center (P30CA015704) and for the University of Virginia Cancer Center (P30CA044579). Publisher Copyright: {\textcopyright}2018 American Association for Cancer Research.",
year = "2018",
month = nov,
doi = "10.1158/2159-8290.CD-18-0385",
language = "English (US)",
volume = "8",
pages = "1422--1437",
journal = "Cancer discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "11",
}