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

• Published in: Clinical cancer research 2020-08, Vol.26 (15), p.4120-4134
• Main Authors: Whittle, James R, Vaillant, François, Surgenor, Elliot, Policheni, Antonia N, Giner, Göknur, Capaldo, Bianca D, Chen, Huei-Rong, Liu, He K, Dekkers, Johanna F, Sachs, Norman, Clevers, Hans, Fellowes, Andrew, Green, Thomas, Xu, Huiling, Fox, Stephen B, Herold, Marco J, Smyth, Gordon K, Gray, Daniel H D, Visvader, Jane E, Lindeman, Geoffrey J
• Format: Article
• Language: English
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-1872

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. 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-derived organoid (PDO), and patient-derived xenograft (PDX) models. A syngeneic ER mouse mammary tumor model was used to study the effect of combination therapy on the immune system. Triple therapy was well tolerated and produced a superior and more durable tumor response compared with single or doublet therapy. This was associated with marked apoptosis, including of senescent cells, indicative of senolysis. Unexpectedly, ABT-199 resulted in Rb dephosphorylation and reduced G -S cyclins, most notably at high doses, thereby intensifying the fulvestrant/palbociclib-induced cell-cycle arrest. Interestingly, a CRISPR/Cas9 screen suggested that ABT-199 could mitigate loss of Rb (and potentially other mechanisms of acquired resistance) to palbociclib. ABT-199 did not abrogate the favorable immunomodulatory effects of palbociclib in a syngeneic ER mammary tumor model and extended tumor response when combined with anti-PD1 therapy. This study illustrates the potential for targeting BCL2 in combination with CDK4/6 inhibitors and supports investigation of combination therapy in ER breast cancer.