Acquired resistance of phosphatase and tensin homolog-deficient cells to poly(ADP-ribose) polymerase inhibitor and Ara-C mediated by 53BP1 loss and SAMHD1 overexpression | |
Wang, Yu-Ting2,3; Yuan, Bo2,3; Chen, Hua-Dong2,3; Xu, Lin2,3; Tian, Yu-Nan2,3; Zhang, Ao1![]() | |
刊名 | CANCER SCIENCE
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2018-03 | |
卷号 | 109期号:3页码:821-831 |
关键词 | 53BP1 acquired resistance phosphatase and tensin homolog deficiency poly(ADP-ribose) polymerase inhibitors SAMHD1 |
ISSN号 | 1349-7006 |
DOI | 10.1111/cas.13477 |
文献子类 | Article |
英文摘要 | With increasing uses of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) for cancer therapy, understanding their resistance is becoming urgent. However, acquired PARPi resistance in the phosphatase and tensin homolog (PTEN)-deficient background is poorly understood. We generated 3 PARPi-resistant PTEN-deficient glioblastoma U251 variants separately with olaparib (U251/OP), talazoparib (U251/TP) and simmiparib (U251/SP). These variants displayed consistent resistance (2.46-71.78-fold) to all 5 PARPi, including niraparib and rucaparib, and showed higher degrees of resistance to the PARPi to which the parental cells were more sensitive. The resistance was characteristic of fast emergence and high stability. However, the resistance acquirement did not cause an increasingly aggressive phenotype. The resistance was not correlated to various factors, including PTEN mutations. The PARPi-treated variants produced less H2AX and G2/M arrest. Consistently, loss of 53BP1 occurred in all variants and its compensation enhanced their sensitivity to PARPi by approximately 76%. The variants revealed slightly different cross-resistance profiles to 13 non-PARPi anticancer drugs. All were resistant to Ara-C (6-8-fold) but showed differential resistance to 5-fluorouracil, gemcitabine and paclitaxel. Almost no resistance was observed to the rest drugs, including cisplatin. SAMHD1 was overexpressed in all the variants and its knockout completely restored their sensitivity to Ara-C but did not affect their PARPi sensitivity. The present study demonstrates a consistent resistance profile to PARPi and a unique cross-resistance profile to non-PARPi drugs in different PARPi-resistant U251 cells and reveals 53BP1 loss and SAMHD1 overexpression as the primary mechanisms responsible for their resistance to PARPi and Ara-C, respectively. These effects probably result from heritable gene change(s) caused by persistent PARPi exposure. |
资助项目 | National Natural Science Foundation of China[81573450] ; National Natural Science Foundation of China[81603160] ; National Natural Science Foundation of China[81773764] ; Chinese Academy of Sciences[29201731121100101] ; Hundred Talents Project[XDA12020104] ; Science and Technology Commission of Shanghai Municipality[16JC1406300] ; State Key Laboratory of Drug Research[SIMM1601ZZ-03] |
WOS关键词 | CONFERS PARP INHIBITOR ; 1ST GLOBAL APPROVAL ; OVARIAN-CARCINOMA ; IN-VIVO ; ANTICANCER ACTIVITY ; BREAST-CANCER ; THERAPY ; PTEN ; NIRAPARIB ; RUCAPARIB |
WOS研究方向 | Oncology |
语种 | 英语 |
出版者 | WILEY |
WOS记录号 | WOS:000426596800035 |
内容类型 | 期刊论文 |
源URL | [http://119.78.100.183/handle/2S10ELR8/279876] ![]() |
专题 | 药理学第一研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
通讯作者 | He, Jin-Xue; Miao, Ze-Hong |
作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Dept Med Chem, Shanghai, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai, Peoples R China; 3.Univ Chinese Acad Sci, Beijing, Peoples R China; |
推荐引用方式 GB/T 7714 | Wang, Yu-Ting,Yuan, Bo,Chen, Hua-Dong,et al. Acquired resistance of phosphatase and tensin homolog-deficient cells to poly(ADP-ribose) polymerase inhibitor and Ara-C mediated by 53BP1 loss and SAMHD1 overexpression[J]. CANCER SCIENCE,2018,109(3):821-831. |
APA | Wang, Yu-Ting.,Yuan, Bo.,Chen, Hua-Dong.,Xu, Lin.,Tian, Yu-Nan.,...&Miao, Ze-Hong.(2018).Acquired resistance of phosphatase and tensin homolog-deficient cells to poly(ADP-ribose) polymerase inhibitor and Ara-C mediated by 53BP1 loss and SAMHD1 overexpression.CANCER SCIENCE,109(3),821-831. |
MLA | Wang, Yu-Ting,et al."Acquired resistance of phosphatase and tensin homolog-deficient cells to poly(ADP-ribose) polymerase inhibitor and Ara-C mediated by 53BP1 loss and SAMHD1 overexpression".CANCER SCIENCE 109.3(2018):821-831. |
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