RB1 loss overrides PARP inhibitor sensitivity driven by RNASEH2B loss in prostate cancer.
RB1 loss overrides PARP inhibitor sensitivity driven by RNASEH2B loss in prostate cancer.
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DOI：
10.1126/sciadv.abl9794
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发表时间：
2022-02-18
期刊：
影响因子：
13.6
通讯作者：
Jia L
中科院分区：
文献类型：
--
作者：
Miao C;Tsujino T;Takai T;Gui F;Tsutsumi T;Sztupinszki Z;Wang Z;Azuma H;Szallasi Z;Mouw KW;Zou L;Kibel AS;Jia L
目前的癌症靶向疗法在很大程度上是由单个基因的突变所引导的，这忽略了同时发生的基因组改变。在此，我们发现RNASEH2B、RB1和BRCA2这三个位于13q染色体上紧密相邻的基因，在前列腺癌中经常单独或共同缺失。RNASEH2B的缺失会使癌细胞因核糖核苷酸切除修复受损和聚（ADP - 核糖）聚合酶（PARP）捕获而对PARP抑制敏感。然而，当与RB1共同缺失时，细胞部分地通过E2F1诱导的BRCA2表达而失去敏感性，从而增强同源重组修复能力。尽管如此，BRCA2的缺失会使RNASEH2B/RB1共同缺失的细胞对PARP抑制重新敏感。我们的研究结果或许可以解释由于多种基因组改变之间的相互作用而导致的PARP抑制在临床结果上的一些差异，并支持通过全面的基因组检测来确定哪些人可能从PARP抑制中获益。最后，我们表明ATR抑制可以破坏E2F1诱导的BRCA2表达，并克服因RB1缺失导致的PARP抑制剂耐药性。
PARP抑制剂敏感性可能取决于多种基因组改变之间的相互作用。
Current targeted cancer therapies are largely guided by mutations of a single gene, which overlooks concurrent genomic alterations. Here, we show that RNASEH2B, RB1, and BRCA2, three closely located genes on chromosome 13q, are frequently deleted in prostate cancer individually or jointly. Loss of RNASEH2B confers cancer cells sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition due to impaired ribonucleotide excision repair and PARP trapping. When co-deleted with RB1, however, cells lose their sensitivity, in part, through E2F1-induced BRCA2 expression, thereby enhancing homologous recombination repair capacity. Nevertheless, loss of BRCA2 resensitizes RNASEH2B/RB1 co-deleted cells to PARP inhibition. Our results may explain some of the disparate clinical results from PARP inhibition due to interaction between multiple genomic alterations and support a comprehensive genomic test to determine who may benefit from PARP inhibition. Last, we show that ATR inhibition can disrupt E2F1-induced BRCA2 expression and overcome PARP inhibitor resistance caused by RB1 loss. PARP inhibitor sensitivity may depend on interaction between multiple genomic alterations.
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