BRCA 突变导致 XIAP 过表达，并使卵巢癌细胞对凋亡抑制剂（IAP）家族抑制剂敏感。

BRCA mutations lead to XIAP overexpression and sensitise ovarian cancer to inhibitor of apoptosis (IAP) family inhibitors.

机构信息

Department of Molecular Medicine, Laboratory of Medical Oncology, Royal College of Surgeons in Ireland, Dublin, Ireland.

Cancer Biology and Stem Cells Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

出版信息

Br J Cancer. 2022 Aug;127(3):488-499. doi: 10.1038/s41416-022-01823-5. Epub 2022 Apr 30.

BACKGROUND

We tested the hypothesis that inhibitor of apoptosis family (IAP) proteins may be altered in BRCA1-mutated ovarian cancers and that could affect the sensitivity to IAP inhibitors.

METHODS

The levels of IAP proteins were evaluated in human cancers and cell lines. Cell lines were used to determine the effects of IAP inhibitors. The in vivo effects of treatments were evaluated in PDX mouse models.

RESULTS

Expression of X-linked inhibitor of apoptosis (XIAP) is increased in BRCA1-mutated cancers and high levels are associated with improved patient outcomes after platinum chemotherapy. XIAP overexpression is mediated by NF-kB activation and is associated with an optimisation of PARP. BRCA1-mutated cell lines are particularly sensitive to IAP inhibitors due to an inhibitory effect on PARP. Both a BRCA1-mutated cell line with acquired resistance to PARP inhibitors and one with restored BRCA1 remain sensitive to IAP inhibitors. Treatment with IAP inhibitors restores the efficacy of PARP inhibition in these cell lines. The IAP inhibitor LCL161 alone and in combination with a PARP inhibitor, exhibited antitumour effects in PDX mouse models of resistant BRCA2 and 1-mutated ovarian cancer, respectively.

CONCLUSION

A clinical trial may be justified to further investigate the utility of IAP inhibitors.

背景

我们检验了这样一个假设，即凋亡抑制因子家族（IAP）蛋白在 BRCA1 突变型卵巢癌中可能发生改变，这可能会影响对 IAP 抑制剂的敏感性。

方法

评估了人类癌症和细胞系中 IAP 蛋白的水平。使用细胞系来确定 IAP 抑制剂的作用。在 PDX 小鼠模型中评估了治疗的体内作用。

结果

凋亡抑制因子（XIAP）的 X 连锁抑制剂表达增加在 BRCA1 突变型癌症中，高水平与铂类化疗后患者预后改善相关。XIAP 的过表达由 NF-κB 激活介导，并与 PARP 的优化相关。由于对 PARP 的抑制作用，BRCA1 突变细胞系对 IAP 抑制剂特别敏感。对 PARP 抑制剂获得耐药性的 BRCA1 突变细胞系和恢复 BRCA1 的细胞系仍然对 IAP 抑制剂敏感。IAP 抑制剂的治疗恢复了这些细胞系中 PARP 抑制的疗效。IAP 抑制剂 LCL161 单独使用以及与 PARP 抑制剂联合使用，在耐药 BRCA2 和 1 突变卵巢癌的 PDX 小鼠模型中分别表现出抗肿瘤作用。