Crebbp Loss Drives Small Cell Lung Cancer and Increases Sensitivity to HDAC Inhibition

Cancer Discovery - Tập 8 Số 11 - Trang 1422-1437 - 2018
Deshui Jia1, Arnaud Augert1, Dong Wook Kim2, Emily Eastwood1, Nan Wu1, Ali H. Ibrahim1, Kee‐Beom Kim2, Colin T. Dunn2, Smitha P.S. Pillai3, Adi F. Gazdar4, Hamid Bolouri1, Kwon-Sik Park2, David MacPherson1,5
11Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
22Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia.
33Division of Comparative Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington.
44The University of Texas Southwestern Medical Center, Hamon Center for Therapeutic Oncology and Department of Pathology, Dallas, Texas.
55Department of Genome Sciences, University of Washington, Seattle, Washington.

Tóm tắt

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. Cancer Discov; 8(11); 1422–37. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333

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Cancer Discovery

Tập 8 Số 11

1422-1437

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