Kinome-Wide RNA Interference Screen Reveals a Role for PDK1 in Acquired Resistance to CDK4/6 Inhibition in ER-Positive Breast Cancer

Cancer Res. 2017 May 1;77(9):2488-2499. doi: 10.1158/0008-5472.CAN-16-2653.

Valerie M Jansen ¹, Neil E Bhola ¹, Joshua A Bauer ² ³, Luigi Formisano ¹, Kyung-Min Lee ¹, Katherine E Hutchinson ¹, Agnieszka K Witkiewicz ⁴, Preston D Moore ¹, Mónica Valéria Estrada ⁵, Violeta Sánchez ⁵, Paula G Ericsson ⁵, Melinda E Sanders ⁶, Paula R Pohlmann ⁷, Michael J Pishvaian ⁷, David A Riddle ¹, Teresa C Dugger ¹, Wenyi Wei ⁸, Erik S Knudsen ⁹, Carlos L Arteaga ¹⁰ ⁵ ¹¹

Affiliations

1 Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
2 Department of Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
3 Vanderbilt Institute of Chemical Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
4 Department of Pathology, University of Arizona, Tucson, Arizona.
5 Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
6 Department of Pathology, Microbiology and Immunology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
7 Department of Medicine, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
8 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
9 Department of Medicine, University of Arizona, Tucson, Arizona.
10 Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. carlos.arteaga@vanderbilt.edu.
11 Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.

PMID: 28249908 DOI: 10.1158/0008-5472.CAN-16-2653

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. Cancer Res; 77(9); 2488-99. ©2017 AACR.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-16297A

Abemaciclib

99.97%, CDK4/6 Inhibitor

CDK

Cancer

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