PTEN inhibition enhances sensitivity of ovarian cancer cells to the poly (ADP-ribose) polymerase inhibitor by suppressing the MRE11-RAD50-NBN complex

• Published in: British journal of cancer 2024-08, Vol.131 (3), p.577-588
• Main Authors: Qiu, Lipeng, Li, Ruyan, Wang, Yue, Lu, Ziwen, Tu, Zhigang, Liu, Hanqing
• Format: Article
• Language: English
• Subjects: 692/4028/67/1059/602; 692/699/67/1517/1709; Acid Anhydride Hydrolases; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; DNA Breaks, Double-Stranded - drug effects; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Double-strand break repair; Drug Resistance; Drug Synergism; Epidemiology; Female; Homologous recombination; Humans; Mice; Molecular Medicine; Molecular modelling; MRE11 Homologue Protein; MRE11 protein; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Phthalazines - pharmacology; Piperazines - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; PTEN protein; Tumor suppressor genes; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-024-02749-w

Background Poly (ADP-ribose) polymerase inhibitors (PARPis) can effectively treat ovarian cancer patients with defective homologous recombination (HR). Loss or dysfunction of PTEN, a typical tumour suppressor, impairs double-strand break (DSB) repair. Hence, we explored the possibility of inhibiting PTEN to induce HR deficiency (HRD) for PARPi application. Methods Functional studies using PTEN inhibitor VO-OHpic and PARPi olaparib were performed to explore the molecular mechanisms in vitro and in vivo. Results In this study, the combination of VO-OHpic with olaparib exhibited synergistic inhibitory effects on ovarian cancer cells was demonstrated. Furthermore, VO-OHpic was shown to enhance DSBs by reducing nuclear expression of PTEN and inhibiting HR repair through the modulation of MRE11-RAD50-NBN (MRN) complex, critical for DSB repair. TCGA and GTEx analysis revealed a strong correlation between PTEN and MRN in ovarian cancer. Mechanistic studies indicated that VO-OHpic reduced expression of MRN, likely by decreasing PTEN/E2F1-mediated transcription. Moreover, PTEN-knockdown inhibited expression of MRN, increased sensitivities to olaparib, and induced DSBs. In vivo experiments showed that the combination of VO-OHpic with olaparib exhibited enhanced inhibitory effects on tumour growth. Conclusions Collectively, this study highlights the potential of PTEN inhibitors in combination therapy with PARPis to create HRD for HRD-negative ovarian cancers.