# Repression of EGFR by new biguanide 4C potentiated ovarian cancer to PARP inhibitors through down-regulation of BRCA2 and Rad51

## TL;DR

A new biguanide compound, 4C, enhances ovarian cancer sensitivity to PARP inhibitors by repressing EGFR and reducing homologous recombination repair.

## Contribution

Discovery that 4C potentiates PARP inhibitor efficacy by targeting EGFR and downregulating BRCA2 and Rad51 in ovarian cancer.

## Key findings

- 4C inhibits homologous recombination and sensitizes BRCA1/2 wild-type ovarian cancer cells to PARP inhibitors.
- EGFR promotes nuclear accumulation of BRCA2 and Rad51 by inhibiting their binding to c-Cbl, reducing PARP inhibitor sensitivity.
- 4C downregulates EGFR, leading to ubiquitination and degradation of BRCA2 and Rad51, thereby increasing PARP inhibitor effectiveness.

## Abstract

EGFR, one of the most successful therapeutic targets, has recently been found to exert a novel function for regulating homologous recombination (HR). Activation of HR is the critical event of treatment failure of PARPi in BRCA1/2 wild-type ovarian cancer (OC). Besides, the antitumor effects of biguanides have also been a focus of attention. Here, we discovered that the new biguanide 4C inhibited HR and sensitized BRCA1/2 wild-type OC cells to PARPi by targeting EGFR. Mechanistically, EGFR promoted nuclear accumulation of both BRCA2 and Rad51, and HR activation by competitively inhibiting the binding of BRCA2 and Rad51 to E3 ubiquitin ligase c-Cbl, thereby reducing cancer cell sensitivity to PARPi following ATM-mediated DNA damage signal transmission from the nucleus to the cytoplasm. Interestingly, EGFR was downregulated by 4C, which in turn enhanced the interaction of BRCA2 and Rad51 with c-Cbl. Consequently, BRCA2 and Rad51 were then ubiquitinated and degraded to inhibit HR and increase the sensitivity of OC to PARPi. Thus, these findings reveal that the combination of 4C with PARPi leading to “synthetic lethality” is an effective strategy for treating BRCA1/2 wild-type OC.