RAD51 inhibition in triple negative breast cancer cells is challenged by compensatory survival signaling and requires rational combination therapy

The strategy of inducing synthetic lethality by targeting defective homologous recombination repair in triple-negative breast cancer (TNBC) has encountered significant challenges. Clinical trials have failed to meet anticipated outcomes, largely due to common resistance mechanisms, such as increased expression of the target gene PARP1, upregulation or reversion mutations in BRCA1, and heightened activity of the compensatory homologous recombination protein RAD51. Notably, RAD51 has been identified as an alternative synthetic lethal target in BRCA1-mutated cancers.
To address the selective pressure imposed on LY2228820 DNA repair pathways, we investigated novel targets in TNBC that exhibit synthetic lethality in conjunction with RAD51 depletion. Our findings confirmed complementary synthetic lethality with PARP1/2 and DNA-PK, as well as a newly identified combination involving p38. p38 represents a relevant therapeutic target in breast cancer, given its role in mediating resistance to chemotherapy, including tamoxifen.
We demonstrate that dual targeting of RAD51 and p38 significantly inhibits cell proliferation both in vitro and in vivo, with further enhancement observed upon concurrent inhibition of PARP1. Mechanistic analysis revealed that RAD51 depletion leads to increased ERK1/2 and p38 signaling, suggesting a compensatory pathway that limits the efficacy of DNA-targeted therapies. These findings underscore the potential of targeting p38 as part of a combinatorial strategy to overcome therapeutic resistance in TNBC.