小柯机器人

英国伦敦癌症研究所Rachael Natrajan小组取得一项新突破。他们发现SF3B1热点突变通过触发复制应激反应缺陷增加对PARP抑制的敏感性。这一研究成果于2023年7月31日发表在国际学术期刊《自然—遗传学》上。

通过合成致死药物筛选，研究人员发现SF3B1突变体（SF3B1^MUT）细胞对聚（ADP-核糖）聚合酶抑制剂（PARPi）具有选择敏感性，这与热点突变和肿瘤部位无关。SF3B1^MUT细胞并不响应PARPi诱导的复制应激，这是通过下调细胞周期蛋白依赖性激酶2相互作用蛋白（CINP）来实现，并导致复制叉起源放电增加和诱导磷酸化CHK1（pCHK1;S317）缺失。

这些会导致无法降解DNA复制中间体和G2/M细胞周期停滞。过表达CINP可弥补这些缺陷，或通过共济失调-毛细血管扩张突变和PARP抑制相结合的方法进一步靶向。在体内，PARPi在多种SF3B1^MUT癌症模型中产生有效的抗肿瘤作用，并消除远处转移。这些数据为在生物标志物诱导的同源重组患者群体中测试PARPi的临床疗效提供了理论基础。

据了解，SF3B1热点突变与几种肿瘤的不良预后有关，并导致经典剪接的整体破坏。

附：英文原文

Title: SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response

Author: Bland, Philip, Saville, Harry, Wai, Patty T., Curnow, Lucinda, Muirhead, Gareth, Nieminuszczy, Jadwiga, Ravindran, Nivedita, John, Marie Beatrix, Hedayat, Somaieh, Barker, Holly E., Wright, James, Yu, Lu, Mavrommati, Ioanna, Read, Abigail, Peck, Barrie, Allen, Mark, Gazinska, Patrycja, Pemberton, Helen N., Gulati, Aditi, Nash, Sarah, Noor, Farzana, Guppy, Naomi, Roxanis, Ioannis, Pratt, Guy, Oldreive, Ceri, Stankovic, Tatjana, Barlow, Samantha, Kalirai, Helen, Coupland, Sarah E., Broderick, Ronan, Alsafadi, Samar, Houy, Alexandre, Stern, Marc-Henri, Pettit, Stephen, Choudhary, Jyoti S., Haider, Syed, Niedzwiedz, Wojciech, Lord, Christopher J., Natrajan, Rachael

Issue&Volume: 2023-07-31

Abstract: SF3B1 hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1 mutant (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUT cells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G2/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1MUT cancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population.

DOI: 10.1038/s41588-023-01460-5

Source: https://www.nature.com/articles/s41588-023-01460-5

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