CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors.
CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors.
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DOI：
10.1186/s13046-022-02570-4
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发表时间：
2022-12-21
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影响因子：
--
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高级别浆液性卵巢癌（HGSC）是上皮性卵巢癌的异质亚型，包括发生在输卵管和腹膜中的浆液性癌。这些癌症现在被细分为同源重组修复（HR）缺陷和熟练亚组，因为这种分类影响管理和预后。PARP抑制剂（PARPi）已显示出显著的临床疗效，特别是在一线和二线背景下，在BRCA突变或同源重组（HR）缺陷型HGSC中对铂类化疗产生应答后作为维持治疗。然而，PARPi在占HGSC近50%的HR熟练HGSC中的临床获益有限，并且由于预后不良且当前标准治疗无效，因此改善这些患者的结局现在是高度优先事项。有许多潜在的研究方向，包括努力使HR熟练的肿瘤对PARPi敏感。在此，我们的目的是通过使用小分子抑制剂CBL 0137与PARPi靶向SSRP 1在HR熟练的HGSC中开发一种新的组合疗法。我们在体外使用一组HGSC细胞系和患者来源的肿瘤细胞测试了CBL 0137单一疗法的抗癌活性。使用RNA测序来绘制CBL 0137处理的患者来源的HR熟练HGSC细胞中的总体转录组学变化。我们使用HGSC细胞系和患者来源的肿瘤细胞在体外和体内测试了CBL 0137与PARPi组合的功效。我们表明，使用小分子CBL 0137将SSRP 1捕获到染色质上的SSRP 1抑制作用在体外对HGSC细胞系和患者来源的肿瘤细胞发挥了显着的抗生长活性，并且还降低了体内肿瘤负荷。CBL 0137通过抑制HR修复途径诱导DNA修复缺陷，并在体外和体内对PARPi、奥拉帕尼致敏SSRP 1-高HR活性HGSC细胞系和患者来源的肿瘤细胞/异种移植物。CBL 0137还增强了HGSC患者来源的异种移植物中DNA损伤铂基化疗的功效。我们的研究结果强烈表明，CBL 0137和PARP抑制的组合代表了表达高水平SSRP 1的HR-熟练HGSC的新治疗策略，并且应该在临床中进行研究。在线版本包含补充材料，可通过10.1186/s13046-022-02570-4获得。
High-grade serous ovarian carcinomas (HGSCs) are a heterogeneous subtype of epithelial ovarian cancers and include serous cancers arising in the fallopian tube and peritoneum. These cancers are now subdivided into homologous recombination repair (HR)-deficient and proficient subgroups as this classification impacts on management and prognosis. PARP inhibitors (PARPi) have shown significant clinical efficacy, particularly as maintenance therapy following response to platinum-based chemotherapy in BRCA-mutant or homologous recombination (HR)-deficient HGSCs in both the 1st and 2nd line settings. However, PARPi have limited clinical benefit in HR-proficient HGSCs which make up almost 50% of HGSC and improving outcomes in these patients is now a high priority due to the poor prognosis with ineffectiveness of the current standard of care. There are a number of potential lines of investigation including efforts in sensitizing HR-proficient tumors to PARPi. Herein, we aimed to develop a novel combination therapy by targeting SSRP1 using a small molecule inhibitor CBL0137 with PARPi in HR-proficient HGSCs. We tested anti-cancer activity of CBL0137 monotherapy using a panel of HGSC cell lines and patient-derived tumor cells in vitro. RNA sequencing was used to map global transcriptomic changes in CBL0137-treated patient-derived HR-proficient HGSC cells. We tested efficacy of CBL0137 in combination with PARPi using HGSC cell lines and patient-derived tumor cells in vitro and in vivo. We show that SSRP1 inhibition using a small molecule, CBL0137, that traps SSRP1 onto chromatin, exerts a significant anti-growth activity in vitro against HGSC cell lines and patient-derived tumor cells, and also reduces tumor burden in vivo. CBL0137 induced DNA repair deficiency via inhibition of the HR repair pathway and sensitized SSRP1-high HR-proficient HGSC cell lines and patient-derived tumor cells/xenografts to the PARPi, Olaparib in vitro and in vivo. CBL0137 also enhanced the efficacy of DNA damaging platinum-based chemotherapy in HGSC patient-derived xenografts. Our findings strongly suggest that combination of CBL0137 and PARP inhibition represents a novel therapeutic strategy for HR-proficient HGSCs that express high levels of SSRP1 and should be investigated in the clinic. The online version contains supplementary material available at 10.1186/s13046-022-02570-4.
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影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
17.1
作者：
Carter DR;Murray J;Cheung BB;Gamble L;Koach J;Tsang J;Sutton S;Kalla H;Syed S;Gifford AJ;Issaeva N;Biktasova A;Atmadibrata B;Sun Y;Sokolowski N;Ling D;Kim PY;Webber H;Clark A;Ruhle M;Liu B;Oberthuer A;Fischer M;Byrne J;Saletta F;Thwe le M;Purmal A;Haderski G;Burkhart C;Speleman F;De Preter K;Beckers A;Ziegler DS;Liu T;Gurova KV;Gudkov AV;Norris MD;Haber M;Marshall GM
通讯作者：
Marshall GM
影响因子：
8.8
作者：
Karakashev S;Zhu H;Yokoyama Y;Zhao B;Fatkhutdinov N;Kossenkov AV;Wilson AJ;Simpkins F;Speicher D;Khabele D;Bitler BG;Zhang R
通讯作者：
Zhang R
DOI：
10.1200/jco.22.01549
发表时间：
2023-01-20
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
通讯作者：
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影响因子：
8.8
作者：
Guffanti, F.;Alvisi, M. F.;Damia, G.
通讯作者：
Damia, G.