Distinct roles of treatment schemes and BRCA2 on the restoration of homologous recombination DNA repair and PARP inhibitor resistance in ovarian cancer.
Distinct roles of treatment schemes and BRCA2 on the restoration of homologous recombination DNA repair and PARP inhibitor resistance in ovarian cancer.
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DOI：
10.1038/s41388-022-02491-8
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发表时间：
2022-11
期刊：
影响因子：
8
通讯作者：
Nair, Jayakumar R.
中科院分区：
文献类型：
--
作者：
Huang, Tzu-Ting;Burkett, Sandra Sczerba;Tandon, Mayank;Yamamoto, Tomomi M.;Gupta, Nitasha;Bitler, Benjamin G.;Lee, Jung-Min;Nair, Jayakumar R.
聚（ADP-核糖）聚合酶抑制剂（PARPis）代表了卵巢癌的一个重大进展，现在作为一种治疗和维持治疗的前期和复发性设置。然而，患者经常对PARPis产生耐药性，这强调了解剖耐药机制的重要性。在这里，我们报告了不同的剂量/时间方案PARPi治疗BRCA 2突变型PEO 1细胞，导致不同的耐药机制的同时发展。通过较高的初始剂量和短期PARPi治疗建立的PARPi耐药变体PEO 1/OlaJR通过快速恢复功能性BRCA 2和促进药物外排活性而产生PARPi耐药性。相比之下，通过较低初始剂量与长期PARPi暴露而开发的PEO 1/OlaR未显示出恢复的BRCA 2功能，但显示出具有更大侵袭能力的间充质样表型，并显示出激活的ATR/CHK 1和抑制的EZH 2/MUS 81信号级联，以分别恢复HR修复和分叉稳定。我们的研究表明，PARPi耐药机制可以通过治疗策略来控制，并具有BRCA 2功能的分子基础。此外，我们定义了不同的机制，可以作为有用的生物标志物来评估PARPi耐药卵巢癌的后续治疗策略。
Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a major advance in ovarian cancer, now as a treatment and as a maintenance therapy in the upfront and recurrent settings. However, patients often develop resistance to PARPis, underlining the importance of dissecting resistance mechanisms. Here, we report different dosing/timing schemes of PARPi treatment in BRCA2-mutant PEO1 cells, resulting in the simultaneous development of distinct resistance mechanisms. PARPi-resistant variants PEO1/OlaJR, established by higher initial doses and short-term PARPi treatment, develops PARPi resistance by rapidly restoring functional BRCA2 and promoting drug efflux activity. In contrast, PEO1/OlaR, developed by lower initial doses with long-term PARPi exposure, shows no regained BRCA2 function but a mesenchymal-like phenotype with greater invasion ability, and exhibits activated ATR/CHK1 and suppressed EZH2/MUS81 signaling cascades to regain HR repair and fork stabilization, respectively. Our study suggests that PARPi resistance mechanisms can be governed by treatment strategies and have a molecular basis on BRCA2 functionality. Further, we define different mechanisms that may serve as useful biomarkers to assess subsequent treatment strategies in PARPi-resistant ovarian cancer.
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影响因子：
3.8
作者：
Haslehurst AM;Koti M;Dharsee M;Nuin P;Evans K;Geraci J;Childs T;Chen J;Li J;Weberpals J;Davey S;Squire J;Park PC;Feilotter H
通讯作者：
Feilotter H
影响因子：
16
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Kolinjivadi AM;Sannino V;De Antoni A;Zadorozhny K;Kilkenny M;Técher H;Baldi G;Shen R;Ciccia A;Pellegrini L;Krejci L;Costanzo V
通讯作者：
Costanzo V
影响因子：
16.8
作者：
Bhat KP;Cortez D
通讯作者：
Cortez D
影响因子：
7.4
作者：
Lee, Jung-Min;Gordon, Nicolas;Kohn, Elise C.
通讯作者：
Kohn, Elise C.
影响因子：
3.8
作者：
D'Andrea, Alan D.
通讯作者：
D'Andrea, Alan D.