Loss of ARID1A Promotes Epithelial–Mesenchymal Transition and Sensitizes Pancreatic Tumors to Proteotoxic Stress A C

Hideo Tomihara, Federica Carbone, Luigi Perelli, Justin K. Huang, Melinda Soeung, Johnathon L. Rose, Frederick S. Robinson, Yonathan Lissanu Deribe, Ningping Feng, Mitsunobu Takeda, Akira Inoue, Edoardo Del Poggetto, Angela K. Deem, Anirban Maitra, Pavlos Msaouel, Nizar M. Tannir, Giulio F. Draetta, Andrea Viale, Timothy P. Heffernan, Christopher A. BristowAlessandro Carugo, Giannicola Genovese

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Cellular dedifferentiation is a key mechanism driving cancer progression. Acquisition of mesenchymal features has been associated with drug resistance, poor prognosis, and disease relapse in many tumor types. Therefore, successful targeting of tumors harboring these characteristics is a priority in oncology practice. The SWItch/Sucrose non-fermentable (SWI/SNF) chromatin remodeling complex has also emerged as a critical player in tumor progression, leading to the identification of several SWI/SNF complex genes as potential disease biomarkers and targets of anticancer therapies. AT-rich interaction domain-containing protein 1A (ARID1A) is a component of SWI/SNF, and mutations in ARID1A represent one of the most frequent molecular alterations in human cancers. ARID1A mutations occur in approximately 10% of pancreatic ductal adenocarcinomas (PDAC), but whether these mutations confer a therapeutic opportunity remains unclear. Here, we demonstrate that loss of ARID1A promotes an epithelial–mesenchymal transition (EMT) phenotype and sensitizes PDAC cells to a clinical inhibitor of HSP90, NVP-AUY922, both in vitro and in vivo. Although loss of ARID1A alone did not significantly affect proliferative potential or rate of apoptosis, ARID1A-deficient cells were sensitized to HSP90 inhibition, potentially by promoting the degradation of intermediate filaments driving EMT, resulting in cell death. Our results describe a mechanistic link between ARID1A defects and a quasi-mesenchymal phenotype, suggesting that deleterious mutations in ARID1A associated with protein loss exhibit potential as a biomarker for patients with PDAC who may benefit by HSP90-targeting drugs treatment. Significance: This study identifies ARID1A loss as a promising biomarker for the identification of PDAC tumors that are potentially responsive to treatment with proteotoxic agents.

Original languageEnglish (US)
Pages (from-to)332-343
Number of pages12
JournalCancer Research
Volume81
Issue number2
DOIs
StatePublished - Jan 15 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Loss of ARID1A Promotes Epithelial–Mesenchymal Transition and Sensitizes Pancreatic Tumors to Proteotoxic Stress A C'. Together they form a unique fingerprint.

Cite this