A HUWE1 defect causes PARP inhibitor resistance by modulating the BRCA1-∆11q splice variant
Although PARP inhibitors (PARPi) are now a standard treatment for cancers with homologous recombination defects, both de novo and acquired resistance limit their overall effectiveness. It has been previously shown that overexpression of the BRCA1-∆11q splice variant contributes to PARPi resistance, but the mechanisms underlying the increased expression of BRCA1-∆11q in cancer cells have remained unclear. Using isogenic cell lines with different BRCA1 mutations, we demonstrate that reduced levels of HUWE1 lead to an increase in BRCA1-∆11q expression and subsequent PARPi resistance. This effect is specific to cells capable of expressing BRCA1-∆11q (such as those with a BRCA1 exon 11 mutation) and is not observed in cells with BRCA1 mutations that cannot produce BRCA1-∆11q, nor in BRCA2 mutant cells. In addition to elevating BRCA1-∆11q protein levels in exon 11 mutant cells, silencing HUWE1 also restores RAD51 nuclear foci formation and platinum salt resistance. Furthermore, mutations in the catalytic domain of HUWE1 were identified in a case of PARPi-resistant, BRCA1 exon 11 mutant, high-grade serous ovarian cancer. These findings suggest a mechanism by which elevated BRCA1-∆11q levels contribute to PARPi resistance, identify HUWE1 as a potential biomarker for assessing PARPi resistance in future clinical trials, and highlight that some resistance mechanisms may only ART0380 be relevant for patients with specific BRCA1 mutations.