Although PARP inhibitors (PARPi) now form part of the standard-of-care for the treatment of homologous recombination defective cancers, de novo and acquired resistance limits their overall effectiveness. Previously, overexpression of the BRCA1-∆11q splice variant has been shown to cause PARPi resistance. How cancer cells achieve increased BRCA1-∆11q expression has remained unclear. Using isogenic cells with different BRCA1 mutations, we show that reduction in HUWE1 leads to increased levels of BRCA1-∆11q and PARPi resistance. This effect is specific to cells able to express BRCA1-∆11q (e.g. BRCA1 exon 11 mutant cells) and is not seen in BRCA1 mutants that cannot express BRCA1-∆11q, nor in BRCA2 mutant cells. As well as increasing levels of BRCA1-∆11q protein in exon 11 mutant cells, HUWE1 silencing also restores RAD51 nuclear foci and platinum salt resistance. HUWE1 catalytic domain mutations were also seen in a case of PARPi resistant, BRCA1 exon 11 mutant, high grade serous ovarian cancer. These results suggest how elevated levels of BRCA1-∆11q and PARPi resistance can be achieved, identify HUWE1 as a candidate biomarker of PARPi resistance for assessment in future clinical trials and illustrate how some PARPi resistance mechanisms may only operate in patients with particular BRCA1 mutations.

尽管 PARP 抑制剂 (PARPi) 现在已成为治疗同源重组缺陷癌症的标准疗法的一部分，但从头和获得性耐药性限制了其整体有效性。此前，BRCA1-Δ11q 剪接变体的过度表达已被证明会导致 PARPi 耐药。癌细胞如何实现 BRCA1-Δ11q 表达增加仍不清楚。使用具有不同BRCA1突变的同基因细胞，我们发现 HUWE1 的减少会导致 BRCA1-Δ11q 和 PARPi 耐药性水平增加。这种效应是能够表达 BRCA1-Δ11q 的细胞（例如BRCA1外显子 11 突变细胞）所特有的，并且在不能表达 BRCA1-Δ11q 的BRCA1突变体或BRCA2突变细胞中未观察到。除了增加外显子 11 突变细胞中 BRCA1-Δ11q 蛋白的水平外，HUWE1 沉默还可以恢复 RAD51 核灶和铂盐抗性。在 PARPi 耐药、 BRCA1外显子 11 突变、高级别浆液性卵巢癌病例中也发现了 HUWE1 催化结构域突变。这些结果表明如何实现 BRCA1-Δ11q 和 PARPi 耐药水平的升高，将 HUWE1 确定为 PARPi 耐药的候选生物标志物，以便在未来的临床试验中进行评估，并说明某些 PARPi 耐药机制如何仅在具有特定 BRCA1 突变的患者中发挥作用。