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Temozolomide Sensitizes ARID1A-Mutated Cancers to PARP Inhibitors.

Publication ,  Journal Article
Yu, Z-C; Li, T; Tully, E; Huang, P; Chen, C-N; Oberdoerffer, P; Gaillard, S; Shih, I-M; Wang, T-L
Published in: Cancer Res
August 15, 2023

UNLABELLED: ARID1A is a subunit of SWI/SNF chromatin remodeling complexes and is mutated in many types of human cancers, especially those derived from endometrial epithelium, including ovarian and uterine clear cell carcinoma (CCC) and endometrioid carcinoma (EMCA). Loss-of-function mutations in ARID1A alter epigenetic regulation of transcription, cell-cycle checkpoint control, and DNA damage repair. We report here that mammalian cells with ARID1A deficiency harbor accumulated DNA base lesions and increased abasic (AP) sites, products of glycosylase in the first step of base excision repair (BER). ARID1A mutations also delayed recruitment kinetics of BER long-patch repair effectors. Although ARID1A-deficient tumors were not sensitive to monotherapy with DNA-methylating temozolomide (TMZ), the combination of TMZ with PARP inhibitors (PARPi) potently elicited double-strand DNA breaks, replication stress, and replication fork instability in ARID1A-deficient cells. The TMZ and PARPi combination also significantly delayed in vivo growth of ovarian tumor xenografts carrying ARID1A mutations and induced apoptosis and replication stress in xenograft tumors. Together, these findings identified a synthetic lethal strategy to enhance the response of ARID1A-mutated cancers to PARP inhibition, which warrants further experimental exploration and clinical trial validation. SIGNIFICANCE: The combination of temozolomide and PARP inhibitor exploits the specific DNA damage repair status of ARID1A-inactivated ovarian cancers to suppress tumor growth.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

August 15, 2023

Volume

83

Issue

16

Start / End Page

2750 / 2762

Location

United States

Related Subject Headings

  • Transcription Factors
  • Temozolomide
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Mammals
  • Humans
  • Female
  • Epigenesis, Genetic
  • DNA-Binding Proteins
 

Citation

APA
Chicago
ICMJE
MLA
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Yu, Z.-C., Li, T., Tully, E., Huang, P., Chen, C.-N., Oberdoerffer, P., … Wang, T.-L. (2023). Temozolomide Sensitizes ARID1A-Mutated Cancers to PARP Inhibitors. Cancer Res, 83(16), 2750–2762. https://doi.org/10.1158/0008-5472.CAN-22-3646
Yu, Zheng-Cheng, Tianhe Li, Ellen Tully, Peng Huang, Chih-Ning Chen, Philipp Oberdoerffer, Stephanie Gaillard, Ie-Ming Shih, and Tian-Li Wang. “Temozolomide Sensitizes ARID1A-Mutated Cancers to PARP Inhibitors.Cancer Res 83, no. 16 (August 15, 2023): 2750–62. https://doi.org/10.1158/0008-5472.CAN-22-3646.
Yu Z-C, Li T, Tully E, Huang P, Chen C-N, Oberdoerffer P, et al. Temozolomide Sensitizes ARID1A-Mutated Cancers to PARP Inhibitors. Cancer Res. 2023 Aug 15;83(16):2750–62.
Yu, Zheng-Cheng, et al. “Temozolomide Sensitizes ARID1A-Mutated Cancers to PARP Inhibitors.Cancer Res, vol. 83, no. 16, Aug. 2023, pp. 2750–62. Pubmed, doi:10.1158/0008-5472.CAN-22-3646.
Yu Z-C, Li T, Tully E, Huang P, Chen C-N, Oberdoerffer P, Gaillard S, Shih I-M, Wang T-L. Temozolomide Sensitizes ARID1A-Mutated Cancers to PARP Inhibitors. Cancer Res. 2023 Aug 15;83(16):2750–2762.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

August 15, 2023

Volume

83

Issue

16

Start / End Page

2750 / 2762

Location

United States

Related Subject Headings

  • Transcription Factors
  • Temozolomide
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Mammals
  • Humans
  • Female
  • Epigenesis, Genetic
  • DNA-Binding Proteins