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

James R. Whittle, François 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 H.D. Gray, Jane E. Visvader, Geoffrey J. Lindeman

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)

Abstract

Purpose: Although cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors significantly extend tumor response in patients with metastatic estrogen receptor–positive (ERþ) 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 ERþ breast cancer cell lines, patient-derived organoid (PDO), and patient-derived xenograft (PDX) models. A syngeneic ERþ mouse mammary tumor model was used to study the effect of combination therapy on the immune system. Results: 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 G1–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 ERþ mammary tumor model and extended tumor response when combined with anti-PD1 therapy. Conclusions: This study illustrates the potential for targeting BCL2 in combination with CDK4/6 inhibitors and supports investigation of combination therapy in ERþ breast cancer.

Original languageEnglish
Pages (from-to)4120-4134
Number of pages15
JournalClinical Cancer Research
Volume26
Issue number15
DOIs
Publication statusPublished - 1 Aug 2020

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