Kinome-Wide RNA Interference Screen Reveals a Role for PDK1 in Acquired Resistance to CDK4/6 Inhibition in ER-Positive Breast Cancer
- Authors
- Jansen, Valerie M.; Bhola, Neil E.; Bauer, Joshua A.; Formisano, Luigi; Lee, Kyung min; Hutchinson, Katherine E.; Witkiewicz, Agnieszka K.; Moore, Preston D.; Estrada, Monica Valeria; Sanchez, Violeta; Ericsson, Paula G.; Sanders, Melinda E.; Pohlmann, Paula R.; Pishvaian, Michael J.; Riddle, David A.; Dugger, Teresa C.; Wei, Wenyi; Knudsen, Erik S.; Arteaga, Carlos L.
- Issue Date
- May-2017
- Publisher
- AMER ASSOC CANCER RESEARCH
- Citation
- CANCER RESEARCH, v.77, no.9, pp.2488 - 2499
- Indexed
- SCIE
SCOPUS
- Journal Title
- CANCER RESEARCH
- Volume
- 77
- Number
- 9
- Start Page
- 2488
- End Page
- 2499
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/142837
- DOI
- 10.1158/0008-5472.CAN-16-2653
- ISSN
- 0008-5472
- 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.
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