Molecular targeted drugs resistance impairs double-strand break repair and sensitizes ER-positive breast cancer to PARP inhibitors
Molecular targeted drugs resistance impairs double-strand break repair and sensitizes ER-positive breast cancer to PARP inhibitors
复制标题
分子靶向药物耐药性损害双链断裂修复并使 ER 阳性乳腺癌对 PARP 抑制剂敏感
DOI：
10.1007/s12282-021-01282-5
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Hayashi S
中科院分区：
文献类型：
--
作者：
Suzuki Y;Wu W;Ohta T;Hayashi S
背景雌激素阳性乳腺癌的治疗方法多种多样，主要有激素治疗和分子靶向药物治疗。获得对这些药物的耐药性是一个主要的临床问题。此外，关于耐药性对DNA修复机制的影响知之甚少。聚ADP核糖聚合酶（PARP）抑制剂目前用于治疗BRCA突变的HER 2阴性转移性乳腺癌，已被证明对同源重组修复受损的BRCA缺陷细胞有效。在这里，我们研究了耐药收购对DNA修复机制和PARP抑制剂对ER（雌激素受体）阳性breast cancer.MethodsWe的影响，研究了在我们实验室建立的各种耐药细胞系的DNA修复机制相关因子的表达和双链断裂（DSB）的修复能力的变化。此外，PARP抑制剂的敏感性进行了研究，使用olaparib.ResultsDSB修复MCF-7和激素治疗耐药模型细胞是正常的，这些细胞表现出低敏感性olaparib。对CDK 4/6抑制剂、氟维司群和mTOR/PI 3 K抑制剂的耐药细胞系显示DSB修复能力降低和奥拉帕尼敏感性高。他们表现出低敏感性CDK 4/6抑制剂，获得耐药CDK 4/6抑制剂和过敏olaparib.ConclusionsOur研究表明，一些情况下获得耐药损害DSB修复能力和敏感ER阳性乳腺癌PARP抑制剂之间的密切联系。
BackgroundThere are various treatments for estrogen-positive breast cancer, mainly hormone therapy and molecular-targeted drugs. Acquiring resistance to these drugs is a major clinical problem. Additionally, little is known about the effect of drug resistance on the DNA repair mechanism. Poly ADP ribose polymerase (PARP) inhibitors currently used for treating HER2-negative metastatic breast cancer withBRCAmutations have been shown to be effective inBRCA-deficient cells with impaired homologous recombination repair. Here, we investigated the effect of drug resistance acquisition on the DNA repair mechanism and the effect of PARP inhibitors on ER (estrogen receptor) -positive breast cancer.MethodsWe investigated changes in the expression of DNA repair mechanism-related factors and repair ability of double-strand breaks (DSB) in various drug-resistant cell lines established in our laboratory. Additionally, PARP inhibitor susceptibility was investigated using olaparib.ResultsDSB repairs in MCF-7 and hormone therapy-resistant model cells were normal, and these cells demonstrated low sensitivity to olaparib. The resistant cell lines against CDK4/6 inhibitors, fulvestrant and mTOR/PI3K inhibitors showed decreased DSB repair ability and high olaparib sensitivity. They showed low sensitivity to CDK4/6 inhibitors, a close link between acquiring resistance to CDK4/6 inhibitors and hypersensitivity to olaparib.ConclusionsOur study suggests some cases of acquiring drug resistance impairs DSB repair ability and sensitizes ER-positive breast cancer to PARP inhibitors.
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影响因子：
19
作者：
Goel S;DeCristo MJ;McAllister SS;Zhao JJ
通讯作者：
Zhao JJ
影响因子：
19
作者：
Zimmerman, Michal;de Lange, Titia
通讯作者：
de Lange, Titia
DOI：
10.1016/j.jsbmb.2013.08.012
发表时间：
2014-01-01
影响因子：
4.1
作者：
Fujiki, Natsu;Konno, Hiromi;Hayashi, Shin-ichi
通讯作者：
Hayashi, Shin-ichi
Abemaciclib 加氟维司群对经内分泌治疗进展的激素受体阳性、ERBB2 阴性乳腺癌总体生存率的影响 — MONARCH 2
影响因子：
28.4
作者：
G. Sledge;M. Toi;P. Neven;J. Sohn;Kenichi Inoue;X. Pivot;O. Burdaeva;M. Okera;N. Masuda;P. Kaufman;H. Koh;E. Grischke;P. Conte;Yi Lu;S. Barriga;K. Hurt;Martin Frenzel;S. Johnston;A. Llombart
通讯作者：
A. Llombart
影响因子：
64.8
作者：
Bryant, HE;Schultz, N;Helleday, T
通讯作者：
Helleday, T