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

Abstract

<div>AbstractPurpose:<p>Although cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors significantly extend tumor response in patients with metastatic estrogen receptor–positive (ER<sup>+</sup>) 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.</p>Experimental Design:<p>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<sup>+</sup> breast cancer cell lines, patient-derived organoid (PDO), and patient-derived xenograft (PDX) models. A syngeneic ER<sup>+</sup> mouse mammary tumor model was used to study the effect of combination therapy on the immune system.</p>Results:<p>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<sub>1</sub>–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<sup>+</sup> mammary tumor model and extended tumor response when combined with anti-PD1 therapy.</p>Conclusions:<p>This study illustrates the potential for targeting BCL2 in combination with CDK4/6 inhibitors and supports investigation of combination therapy in ER<sup>+</sup> breast cancer.</p></div>