TY - JOUR
T1 - Loss of ARID1A Promotes Epithelial–Mesenchymal Transition and Sensitizes Pancreatic Tumors to Proteotoxic Stress A C
AU - Tomihara, Hideo
AU - Carbone, Federica
AU - Perelli, Luigi
AU - Huang, Justin K.
AU - Soeung, Melinda
AU - Rose, Johnathon L.
AU - Robinson, Frederick S.
AU - Deribe, Yonathan Lissanu
AU - Feng, Ningping
AU - Takeda, Mitsunobu
AU - Inoue, Akira
AU - Poggetto, Edoardo Del
AU - Deem, Angela K.
AU - Maitra, Anirban
AU - Msaouel, Pavlos
AU - Tannir, Nizar M.
AU - Draetta, Giulio F.
AU - Viale, Andrea
AU - Heffernan, Timothy P.
AU - Bristow, Christopher A.
AU - Carugo, Alessandro
AU - Genovese, Giannicola
N1 - Publisher Copyright:
©2020 American Association for Cancer Research.
PY - 2021/1/15
Y1 - 2021/1/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-19-3922
DO - 10.1158/0008-5472.CAN-19-3922
M3 - Article
C2 - 33158812
AN - SCOPUS:85100422176
SN - 0008-5472
VL - 81
SP - 332
EP - 343
JO - Cancer Research
JF - Cancer Research
IS - 2
ER -