Kinome-Wide RNA Interference Screen Reveals a Role for PDK1 in Acquired Resistance to CDK4/6 Inhibition in ER-Positive Breast Cancer
DC Field | Value | Language |
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dc.contributor.author | Jansen, Valerie M. | - |
dc.contributor.author | Bhola, Neil E. | - |
dc.contributor.author | Bauer, Joshua A. | - |
dc.contributor.author | Formisano, Luigi | - |
dc.contributor.author | Lee, Kyung min | - |
dc.contributor.author | Hutchinson, Katherine E. | - |
dc.contributor.author | Witkiewicz, Agnieszka K. | - |
dc.contributor.author | Moore, Preston D. | - |
dc.contributor.author | Estrada, Monica Valeria | - |
dc.contributor.author | Sanchez, Violeta | - |
dc.contributor.author | Ericsson, Paula G. | - |
dc.contributor.author | Sanders, Melinda E. | - |
dc.contributor.author | Pohlmann, Paula R. | - |
dc.contributor.author | Pishvaian, Michael J. | - |
dc.contributor.author | Riddle, David A. | - |
dc.contributor.author | Dugger, Teresa C. | - |
dc.contributor.author | Wei, Wenyi | - |
dc.contributor.author | Knudsen, Erik S. | - |
dc.contributor.author | Arteaga, Carlos L. | - |
dc.date.accessioned | 2022-07-07T03:54:34Z | - |
dc.date.available | 2022-07-07T03:54:34Z | - |
dc.date.created | 2021-05-14 | - |
dc.date.issued | 2017-05 | - |
dc.identifier.issn | 0008-5472 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/142837 | - |
dc.description.abstract | Acquired resistance to cyclin-dependent kinases 4 and 6 (CDK4/6) small-molecule inhibitors in breast cancer arises through mechanisms that are yet uncharacterized. In this study, we used a kinome-wide siRNA screen to identify kinases that, when downregulated, yield sensitivity to the CDK4/6 inhibitor ribociclib. In this manner, we identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as a key modifier of ribociclib sensitivity in estrogen receptor–positive MCF-7 breast cancer cells. Pharmacologic inhibition of PDK1 with GSK2334470 in combination with ribociclib or palbociclib, another CDK4/6 inhibitor, synergistically inhibited proliferation and increased apoptosis in a panel of ER-positive breast cancer cell lines. Ribociclib-resistant breast cancer cells selected by chronic drug exposure displayed a relative increase in the levels of PDK1 and activation of the AKT pathway. Analysis of these cells revealed that CDK4/6 inhibition failed to induce cell-cycle arrest or senescence. Mechanistic investigations showed that resistant cells coordinately upregulated expression of cyclins A, E, and D1, activated phospho-CDK2, and phospho-S477/T479 AKT. Treatment with GSK2334470 or the CDK2 inhibitor dinaciclib was sufficient to reverse these events and to restore the sensitivity of ribociclib-resistant cells to CDK4/6 inhibitors. Ribociclib, in combination with GSK2334470 or the PI3Kα inhibitor alpelisib, decreased xenograft tumor growth more potently than each drug alone. Taken together, our results highlight a role for the PI3K–PDK1 signaling pathway in mediating acquired resistance to CDK4/6 inhibitors. | - |
dc.language | 영어 | - |
dc.language.iso | en | - |
dc.publisher | AMER ASSOC CANCER RESEARCH | - |
dc.title | Kinome-Wide RNA Interference Screen Reveals a Role for PDK1 in Acquired Resistance to CDK4/6 Inhibition in ER-Positive Breast Cancer | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Lee, Kyung min | - |
dc.identifier.doi | 10.1158/0008-5472.CAN-16-2653 | - |
dc.identifier.scopusid | 2-s2.0-85018607476 | - |
dc.identifier.wosid | 000400270100029 | - |
dc.identifier.bibliographicCitation | CANCER RESEARCH, v.77, no.9, pp.2488 - 2499 | - |
dc.relation.isPartOf | CANCER RESEARCH | - |
dc.citation.title | CANCER RESEARCH | - |
dc.citation.volume | 77 | - |
dc.citation.number | 9 | - |
dc.citation.startPage | 2488 | - |
dc.citation.endPage | 2499 | - |
dc.type.rims | ART | - |
dc.type.docType | 정기학술지(Article(Perspective Article포함)) | - |
dc.description.journalClass | 1 | - |
dc.description.isOpenAccess | N | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Oncology | - |
dc.relation.journalWebOfScienceCategory | Oncology | - |
dc.subject.keywordPlus | PROTEIN-KINASE B | - |
dc.subject.keywordPlus | CELL-CULTURE | - |
dc.subject.keywordPlus | ACTIVATION | - |
dc.subject.keywordPlus | PHOSPHORYLATION | - |
dc.subject.keywordPlus | SENSITIVITY | - |
dc.subject.keywordPlus | COMBINATION | - |
dc.subject.keywordPlus | PALBOCICLIB | - |
dc.subject.keywordPlus | PACLITAXEL | - |
dc.subject.keywordPlus | LETROZOLE | - |
dc.subject.keywordPlus | SURVIVAL | - |
dc.identifier.url | https://aacrjournals.org/cancerres/article/77/9/2488/625127/Kinome-Wide-RNA-Interference-Screen-Reveals-a-Role | - |
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