2. Academic Validation
  3. ALDH1A1 Contributes to PARP Inhibitor Resistance via Enhancing DNA Repair in BRCA2-/- Ovarian Cancer Cells

ALDH1A1 Contributes to PARP Inhibitor Resistance via Enhancing DNA Repair in BRCA2-/- Ovarian Cancer Cells

  • Mol Cancer Ther. 2020 Jan;19(1):199-210. doi: 10.1158/1535-7163.MCT-19-0242.
Lu Liu  # 1 2 3,  Shurui Cai  # 2 3,  Chunhua Han 2 3,  Ananya Banerjee 2 3 4,  Dayong Wu 2 3,  Tiantian Cui 2 3,  Guozhen Xie 2 3,  Junran Zhang 2 3,  Xiaoli Zhang 5,  Eric McLaughlin 5,  Ming Yin 6,  Floor J Backes 7,  Arnab Chakravarti 2 3,  Yanfang Zheng 8,  Qi-En Wang 9 3
Affiliations

Affiliations

  • 1 Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 2 Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, Ohio.
  • 3 The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
  • 4 School of Biotechnology, KIIT Deemed to Be University, Bhubaneswar, Odisha, India.
  • 5 Center for Biostatistics, Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, Ohio.
  • 6 Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio.
  • 7 Department of Obstetrics and Gynecology, College of Medicine, The Ohio State University, Columbus, Ohio.
  • 8 Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China. [email protected] [email protected].
  • 9 Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, Ohio. [email protected] [email protected].
  • # Contributed equally.
PMID: 31534014 DOI: 10.1158/1535-7163.MCT-19-0242
Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved to treat recurrent ovarian Cancer with BRCA1 or BRCA2 mutations, and as maintenance therapy for recurrent platinum-sensitive ovarian Cancer (BRCA wild-type or mutated) after treatment with platinum. However, the acquired resistance against PARPi remains a clinical hurdle. Here, we demonstrated that PARP Inhibitor (olaparib)-resistant epithelial ovarian Cancer (EOC) cells exhibited an elevated aldehyde dehydrogenase (ALDH) activity, mainly contributed by increased expression of ALDH1A1 due to olaparib-induced expression of BRD4, a member of bromodomain and extraterminal (BET) family protein. We also revealed that ALDH1A1 enhanced microhomology-mediated end joining (MMEJ) activity in EOC cells with inactivated BRCA2, a key protein that promotes homologous recombination (HR) by using an intrachromosomal MMEJ reporter. Moreover, NCT-501, an ALDH1A1-selective inhibitor, can synergize with olaparib in killing EOC cells carrying BRCA2 mutation in both in vitro Cell Culture and the in vivo xenograft animal model. Given that MMEJ activity has been reported to be responsible for PARPi resistance in HR-deficient cells, we conclude that ALDH1A1 contributes to the resistance to PARP inhibitors via enhancing MMEJ in BRCA2-/- ovarian Cancer cells. Our findings provide a novel mechanism underlying PARPi resistance in BRCA2-mutated EOC cells and suggest that inhibition of ALDH1A1 could be exploited for preventing and overcoming PARPi resistance in EOC patients carrying BRCA2 mutation.

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