Rehman, Hasibur ORCID: 0000-0003-1551-6520, Chandrashekar, Darshan S., Balabhadrapatruni, Chakravarthi, Nepal, Saroj, Balasubramanya, Sai Akshaya Hodigere, Shelton, Abigail K., Skinner, Kasey R., Ma, Ai-Hong ORCID: 0000-0001-9798-164X, Rao, Ting, Agarwal, Sumit, Eich, Marie-Lisa ORCID: 0000-0002-8601-4598, Robinson, Alyncia D., Naik, Gurudatta, Manne, Upender, Netto, George J., Miller, C. Ryan, Pan, Chong-Xian, Sonpavde, Guru, Varambally, Sooryanarayana and Ferguson, James E., III (2022). ARID1A-deficient bladder cancer is dependent on PI3K signaling and sensitive to EZH2 and PI3K inhibitors. JCI Insight, 7 (16). ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 2379-3708

Full text not available from this repository.

Abstract

Metastatic urothelial carcinoma is generally incurable with current systemic therapies. Chromatin modifiers are frequently mutated in bladder cancer, with ARID1A-inactivating mutations present in about 20% of tumors. EZH2, a histone methyltransferase, acts as an oncogene that functionally opposes ARID1A. In addition, PI3K signaling is activated in more than 20% of bladder cancers. Using a combination of in vitro and in vivo data, including patient-derived xenografts, we show that ARID1A-mutant tumors were more sensitive to EZH2 inhibition than ARID1A WT tumors. Mechanistic studies revealed that (a) ARID1A deficiency results in a dependency on PI3K/ AKT/mTOR signaling via upregulation of a noncanonical PI3K regulatory subunit, PIK3R3, and downregulation of MAPK signaling and (b) EZH2 inhibitor sensitivity is due to upregulation of PIK3IP1, a protein inhibitor of PI3K signaling. We show that PIK3IP1 inhibited PI3K signaling by inducing proteasomal degradation of PIK3R3. Furthermore, ARID1A-deficient bladder cancer was sensitive to combination therapies with EZH2 and PI3K inhibitors in a synergistic manner. Thus, our studies suggest that bladder cancers with ARID1A mutations can be treated with inhibitors of EZH2 and/or PI3K and revealed mechanistic insights into the role of noncanonical PI3K constituents in bladder cancer biology.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rehman, HasiburUNSPECIFIEDorcid.org/0000-0003-1551-6520UNSPECIFIED
Chandrashekar, Darshan S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Balabhadrapatruni, ChakravarthiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nepal, SarojUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Balasubramanya, Sai Akshaya HodigereUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shelton, Abigail K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Skinner, Kasey R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ma, Ai-HongUNSPECIFIEDorcid.org/0000-0001-9798-164XUNSPECIFIED
Rao, TingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Agarwal, SumitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eich, Marie-LisaUNSPECIFIEDorcid.org/0000-0002-8601-4598UNSPECIFIED
Robinson, Alyncia D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Naik, GurudattaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Manne, UpenderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Netto, George J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miller, C. RyanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pan, Chong-XianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sonpavde, GuruUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Varambally, SooryanarayanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferguson, James E., IIIUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-691908
DOI: 10.1172/jci.insight.155899
Journal or Publication Title: JCI Insight
Volume: 7
Number: 16
Date: 2022
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Place of Publication: ANN ARBOR
ISSN: 2379-3708
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GROUP PROTEIN EZH2; PHOSPHATIDYLINOSITOL 3-KINASE; TARGETING EZH2; OPEN-LABEL; PATHWAY; PROLIFERATION; TAZEMETOSTAT; REPRESSION; PIK3IP1; RNAMultiple languages
Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69190

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item