SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response.
SF3B1 hotspot mutations confer sensitivity to PARP inhibition by eliciting a defective replication stress response.
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DOI：
10.1038/s41588-023-01460-5
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发表时间：
2023-08
期刊：
影响因子：
30.8
通讯作者：
Natrajan, Rachael
中科院分区：
文献类型：
--
作者：
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
在一些肿瘤类型中，SF3B1热点突变与预后不良有关，并导致规范剪接的全局中断。通过人工合成致死药物筛选，我们发现SF3B1突变(SF3B1MUT)细胞对聚(ADP-核糖)聚合酶抑制剂(PARPI)选择性敏感，与热点突变和肿瘤部位无关。SF3B1MUT细胞对PARPI诱导的复制应激表现出缺陷的反应，这种反应是通过下调周期蛋白依赖的蛋白2相互作用蛋白(CINP)发生的，导致复制叉源激发增加和磷酸化CHK1(pCHK1；S317)诱导的丢失。这导致随后无法解析DNA复制中间产物和G2/M细胞周期停滞。这些缺陷可以通过CINP的过度表达来修复，或者通过突变的共济失调-毛细血管扩张和PARP抑制的组合来进一步靶向。在体内，PARPI在多种SF3B1MUT肿瘤模型中产生深刻的抗肿瘤作用，并消除远处转移。这些数据为在生物标记物驱动的同源重组熟练患者群体中测试PARPI的临床疗效提供了理论基础。SF3B1突变使人对聚(ADP-核糖)聚合酶抑制剂(PARPI)敏感。从机制上讲，这不依赖于同源重组修复，而是依赖于由于细胞周期蛋白依赖的蛋白2相互作用蛋白(CINP)减少而导致的缺陷复制应激反应。PARPI处理SF3B1突变(SF3B1MUT)肿瘤会导致复制应激，这种复制应激是由分叉起源激发增加而引起的，最终导致细胞周期停滞。
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. SF3B1 mutations confer sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi). Mechanistically, this is independent of homologous recombination repair and instead relies on a defective replication stress response due to a reduction of the cyclin-dependent kinase 2 interacting protein (CINP). PARPi treatment of SF3B1 mutant (SF3B1MUT) tumors leads to replication stress induced by increased fork origin firing and culminates in cell cycle stalling.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
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作者：
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作者：
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