{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T18:19:43Z","timestamp":1773512383060,"version":"3.50.1"},"reference-count":44,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,1,30]],"date-time":"2018-01-30T00:00:00Z","timestamp":1517270400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81573450"],"award-info":[{"award-number":["81573450"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81603160"],"award-info":[{"award-number":["81603160"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81773764"],"award-info":[{"award-number":["81773764"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002367","name":"Chinese Academy of Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002367","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003399","name":"Science and Technology Commission of Shanghai Municipality","doi-asserted-by":"publisher","award":["16JC1406300"],"award-info":[{"award-number":["16JC1406300"]}],"id":[{"id":"10.13039\/501100003399","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2018,3]]},"abstract":"With increasing uses of poly(ADP<\/jats:styled-content>\u2010ribose) polymerase (PARP<\/jats:styled-content>) inhibitors (PARP<\/jats:styled-content>i) for cancer therapy, understanding their resistance is becoming urgent. However, acquired PARP<\/jats:styled-content>i resistance in the phosphatase and tensin homolog (PTEN<\/jats:styled-content>)\u2010deficient background is poorly understood. We generated 3 PARP<\/jats:styled-content>i\u2010resistant PTEN<\/jats:styled-content>\u2010deficient glioblastoma U251 variants separately with olaparib (U251\/OP<\/jats:styled-content>), talazoparib (U251\/TP<\/jats:styled-content>) and simmiparib (U251\/SP<\/jats:styled-content>). These variants displayed consistent resistance (2.46\u201071.78\u2010fold) to all 5 PARP<\/jats:styled-content>i, including niraparib and rucaparib, and showed higher degrees of resistance to the PARP<\/jats:styled-content>i 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<\/jats:styled-content><\/jats:italic> mutations. The PARP<\/jats:styled-content>i\u2010treated variants produced less \u03b3H2AX<\/jats:styled-content> and G2\/M arrest. Consistently, loss of 53BP<\/jats:styled-content>1 occurred in all variants and its compensation enhanced their sensitivity to PARP<\/jats:styled-content>i by approximately 76%. The variants revealed slightly different cross\u2010resistance profiles to 13 non\u2010PARP<\/jats:styled-content>i anticancer drugs. All were resistant to Ara\u2010C (6\u20108\u2010fold) but showed differential resistance to 5\u2010fluorouracil, gemcitabine and paclitaxel. Almost no resistance was observed to the rest drugs, including cisplatin. SAMHD<\/jats:styled-content>1 was overexpressed in all the variants and its knockout completely restored their sensitivity to Ara\u2010C but did not affect their PARP<\/jats:styled-content>i sensitivity. The present study demonstrates a consistent resistance profile to PARP<\/jats:styled-content>i and a unique cross\u2010resistance profile to non\u2010PARP<\/jats:styled-content>i drugs in different PARP<\/jats:styled-content>i\u2010resistant U251 cells and reveals 53BP<\/jats:styled-content>1 loss and SAMHD<\/jats:styled-content>1 overexpression as the primary mechanisms responsible for their resistance to PARP<\/jats:styled-content>i and Ara\u2010C, respectively. These effects probably result from heritable gene change(s) caused by persistent PARP<\/jats:styled-content>i exposure.<\/jats:p>","DOI":"10.1111\/cas.13477","type":"journal-article","created":{"date-parts":[[2017,12,24]],"date-time":"2017-12-24T10:09:01Z","timestamp":1514110141000},"page":"821-831","source":"Crossref","is-referenced-by-count":18,"title":["Acquired resistance of phosphatase and tensin homolog\u2010deficient cells to poly(ADP\u2010ribose) polymerase inhibitor and Ara\u2010C mediated by 53BP1 loss and SAMHD1 overexpression"],"prefix":"10.1111","volume":"109","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8304-4898","authenticated-orcid":false,"given":"Yu\u2010Ting","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Anti\u2010Tumor Pharmacology State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China"},{"name":"University of Chinese Academy of Sciences Beijing 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