ALDH1A1 promotes PARP inhibitor resistance by enhancing retinoic acid receptor-mediated DNA polymerase θ expression

Kousalya Lavudi; Ananya Banerjee; Na Li; Yajing Yang; Shurui Cai; Xuetao Bai; Xiaoli Zhang; Aidan Li; Elsa Wani; Shyh-Ming Yang; Junran Zhang; Ganesha Rai; Floor Backes; Srinivas Patnaik; Peixuan Guo; Qi-En Wang

doi:10.1038/s41698-023-00411-x

ALDH1A1 promotes PARP inhibitor resistance by enhancing retinoic acid receptor-mediated DNA polymerase θ expression

NPJ Precis Oncol. 2023 Jul 10;7(1):66. doi: 10.1038/s41698-023-00411-x.

Authors

Kousalya Lavudi^{1

2}, Ananya Banerjee^{1

2}, Na Li^{1

2}, Yajing Yang^{1

2}, Shurui Cai^{1

2}, Xuetao Bai^{1

2}, Xiaoli Zhang³, Aidan Li⁴, Elsa Wani¹, Shyh-Ming Yang⁵, Junran Zhang^{1

2}, Ganesha Rai⁵, Floor Backes⁶, Srinivas Patnaik⁷, Peixuan Guo^{1

8}, Qi-En Wang^{9

10}

Affiliations

¹ Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
² Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA.
³ Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
⁴ Washington University in St. Louis, St. Louis, MO, 63130, USA.
⁵ Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, 20850, USA.
⁶ Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
⁷ School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar, Odisha, 751024, India.
⁸ Center for RNA Nanobiotechnology and Nanomedicine, Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, 43210, USA.
⁹ Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA. qi-en.wang@osumc.edu.
¹⁰ Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA. qi-en.wang@osumc.edu.

Abstract

Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPi) have been approved for both frontline and recurrent setting in ovarian cancer with homologous recombination (HR) repair deficiency. However, more than 40% of BRCA1/2-mutated ovarian cancer lack the initial response to PARPi treatment, and the majority of those that initially respond eventually develop resistance. Our previous study has demonstrated that increased expression of aldehyde dehydrogenase 1A1 (ALDH1A1) contributes to PARPi resistance in BRCA2-mutated ovarian cancer cells by enhancing microhomology-mediated end joining (MMEJ) but the mechanism remains unknown. Here, we find that ALDH1A1 enhances the expression of DNA polymerase θ (Polθ, encoded by the POLQ gene) in ovarian cancer cells. Furthermore, we demonstrate that the retinoic acid (RA) pathway is involved in the transcription activation of the POLQ gene. The RA receptor (RAR) can bind to the retinoic acid response element (RARE) located in the promoter of the POLQ gene, promoting transcription activation-related histone modification in the presence of RA. Given that ALDH1A1 catalyzes the biosynthesis of RA, we conclude that ALDH1A1 promotes POLQ expression via the activation of the RA signaling pathway. Finally, using a clinically-relevant patient-derived organoid (PDO) model, we find that ALDH1A1 inhibition by the pharmacological inhibitor NCT-505 in combination with the PARP inhibitor olaparib synergistically reduce the cell viability of PDOs carrying BRCA1/2 mutation and positive ALDH1A1 expression. In summary, our study elucidates a new mechanism contributing to PARPi resistance in HR-deficient ovarian cancer and shows the therapeutic potential of combining PARPi and ALDH1A1 inhibition in treating these patients.

Abstract

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