Journal article

Dual Targeting of CDK4/6 and BCL2 Pathways Augments Tumor Response in Estrogen Receptor-Positive Breast Cancer

James R Whittle, Francois Vaillant, Elliot Surgenor, Antonia N Policheni, Goknur Giner, Bianca D Capaldo, Huei-Rong Chen, He K Liu, Johanna F Dekkers, Norman Sachs, Hans Clevers, Andrew Fellowes, Thomas Green, Huiling Xu, Stephen B Fox, Marco J Herold, Gordon K Smyth, Daniel HD Gray, Jane E Visvader, Geoffrey J Lindeman



PURPOSE: Although cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors significantly extend tumor response in patients with metastatic estrogen receptor-positive (ER+) breast cancer, relapse is almost inevitable. This may, in part, reflect the failure of CDK4/6 inhibitors to induce apoptotic cell death. We therefore evaluated combination therapy with ABT-199 (venetoclax), a potent and selective BCL2 inhibitor. EXPERIMENTAL DESIGN: BCL2 family member expression was assessed following treatment with endocrine therapy and the CDK4/6 inhibitor palbociclib. Functional assays were used to determine the impact of adding ABT-199 to fulvestrant and palbociclib in ER+ breast cancer cell lines, patient-..

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Awarded by National Health and Medical Research Council, Australia

Awarded by National Breast Cancer Foundation

Awarded by Breast Cancer Research Foundation

Awarded by Cancer Australia

Awarded by Collie Foundation

Awarded by NHMRC Research Fellowships

Funding Acknowledgements

We are grateful to G.B. Mann, L. Graham, and staff at the Royal Melbourne Hospital Tissue Bank for support and thank the Animal, Histology and FACS services at WEHI. We thank A. Strasser for helpful discussions. Coded breast tumor samples were provided by the Victorian Cancer Biobank (which is supported by the Victorian Government). This work was supported by theNational Health and Medical Research Council, Australia (NHMRC 1054618, 1113133, 1153049), NHMRC IRIISS, Victorian State Government Operational Infrastructure Support, Australian Cancer Research Foundation, National Breast Cancer Foundation (NT-13-06, IIRS-19004), Breast Cancer Research Foundation (BCRF-18-182), Cancer Australia 1165878), Qualtrough Cancer Research Fund, Joan Marshall Breast Cancer Research Fund, and Collie Foundation (2017F001). J.R. Whittle was supported by an NHMRC/NBCF Research Fellowship and the Royal Australasian College of Physicians, A.N. Policheni by a Cancer Council Victoria Postdoctoral Research Fellowship, J.F. Dekkers by a Marie-Curie Postdoctoral Fellowship, and NHMRC Research Fellowships to D.H.D. Gray (1090236 and 1158024), G.K. Smyth (1058892), J.E. Visvader (1037230), and G.J. Lindeman (1078730 and 1175960).