Journal
CLINICAL CANCER RESEARCH
Volume 26, Issue 15, Pages 4120-4134Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-19-1872
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Funding
- Victorian Government
- National 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
- Collie Foundation [2017F001]
- NHMRC/NBCF Research Fellowship
- Royal Australasian College of Physicians
- Cancer Council Victoria Postdoctoral Research Fellowship
- Marie-Curie Postdoctoral Fellowship
- NHMRC Research Fellowships [1090236, 1158024, 1058892, 1037230, 1078730, 1175960]
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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-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. 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 G(1)-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. Conclusions: This study illustrates the potential for targeting BCL2 in combination with CDK4/6 inhibitors and supports investigation of combination therapy in ER+ breast cancer.
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