Abstract
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 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 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.
Highlights
Estrogen receptor–positive (ERþ) breast cancers frequently exhibit deregulation of the cyclin-dependent kinase 4 and 6 (CDK4/6)/cyclin D1 (CCND1)/retinoblastoma (Rb) signaling pathway, resulting in uncontrolled cellular proliferation [1, 2]
This study illustrates the potential for targeting BCL2 in combination with CDK4/6 inhibitors and supports investigation of combination therapy in ERþ breast cancer
To gain insight into the short-term effects of combined endocrine and CDK4/6 inhibitor therapy on BCL2 prosurvival family members in treatment-na€ve breast cancer, we evaluated gene expression data from the NeoPalAna window study [27], in which patients with newly diagnosed ERþ breast cancer were treated with the aromatase inhibitor anastrozole followed by the CDK4/6 inhibitor palbociclib prior to surgery (Fig. 1A; Supplementary Fig. S1A)
Summary
Estrogen receptor–positive (ERþ) breast cancers frequently exhibit deregulation of the cyclin-dependent kinase 4 and 6 (CDK4/6)/cyclin D1 (CCND1)/retinoblastoma (Rb) signaling pathway, resulting in uncontrolled cellular proliferation [1, 2]. Combination treatment with endocrine therapy and a CDK4/6 inhibitor is considered standard of care for patients with early-line metastatic ERþ breast cancer. The profound cell-cycle arrest has been linked to induction of a senescence program [10] Despite their potent antiproliferative effects and demonstrated efficacy in the clinic, CDK4/6 inhibitors do not induce apoptotic cell death in breast cancer cells [7, 10, 11]. Recent findings suggest that combination therapy may reduce apoptosis in treatment-na€ve tumors [12] These findings are consistent with the senescent state, characterized by relatively irreversible replicative arrest and resistance to apoptosis [13, 14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
