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Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are standard of care in combination with endocrine therapy in advanced hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Despite improved progression-free and overall survival, almost all patients develop CDK4/6 inhibitor resistance and experience disease progression on treatment. Aberrant activation of CDK2/cyclin E is a key resistance mechanism by which tumors can evade CDK4/6 blockade. Therefore, patients with HR+/HER2- breast cancer could benefit from treatment with a selective CDK2 inhibitor in combination with CDK4/6 inhibitors both in the resistant and first-line (1L) settings. BLU-222 is a novel, potent, and selective small-molecule inhibitor of CDK2 with favorable pharmacokinetic properties when administered orally, currently in early-stage clinical development. In pre-clinical studies using the MCF-7 xenograft model of HR+ CDK4/6-responsive breast cancer, treatment with BLU-222 combined with the CDK4/6 inhibitor ribociclib led to pronounced and durable tumor regression superior to ribociclib alone. In a derived palbociclib resistant MCF-7 xenograft model, ribociclib had no anti-tumor activity while BLU-222 led to a strong and durable anti-tumor response (83% tumor growth inhibition [TGI]) that was further improved when given in combination with ribociclib (110% TGI). To further explore the mechanism of aberrant CDK2 activation in CDK4/6 resistant, HR+ breast cancer, we engineered isogenic T47D cell lines to overexpress cyclin E1 (CCNE1) with or without p16, an endogenous inhibitor of CDK4/6 activity. In in vitro proliferation assays, co-expression of CCNE1 and p16 sensitized T47D cells to BLU-222 by approximately 10-fold compared to the parental control (110 nM vs 1078 nM, respectively). CDK4/6 inhibition with ribociclib had no anti-proliferative effect in the CCNE1 overexpressing cell lines regardless of p16 expression status. In vivo, treatment of the empty vector control T47D xenografts with ribociclib led to tumor stasis, while ribociclib in combination with BLU-222 led to tumor regression. T47D xenografts overexpressing both CCNE1 and p16 were resistant to ribociclib however CDK2 inhibition with BLU-222 single-agent treatment led to tumor regression. Finally, the activity of BLU-222 was evaluated in a patient-derived xenograft (PDX) model of CDK4/6 inhibitor-resistant HR+/HER2- breast cancer where the patient had progressed on 1L palbociclib/fulvestrant and 2L abemaciclib/fulvestrant therapy. In this PDX model, BLU-222 in combination with ribociclib led to tumor stasis, even in the absence of fulvestrant. In conclusion, these data support CDK2/cyclin E activation as a key vulnerability in CDK4/6 resistant, HR+/HER2- breast cancer and provide a rationale for the study of BLU-222 in patients with disease progression following CDK4/6 inhibitor treatment. Additionally, the improved durability of response when BLU-222 is combined with CDK4/6 inhibitors in the CDK4/6-naïve setting supports the combination of these agents as 1L treatment. BLU-222 is currently under investigation in VELA (NCT05252416), a phase 1/2, first-in-human trial for patients with cyclin E aberrant cancers and HR+/HER2- breast cancer. Citation Format: Victoria Brown, Nealia House, Phil Ramsden, Karen Ho, Hsin-Jung Wu, Erik Wilker, Jian Guo, Maxine Chen, Douglas Wilson, Neil Bifulco, Steve Wenglowsky, Yoon Jong Choi, Kerrie Faia. CDK2 inhibition with BLU-222 in combination with ribociclib demonstrates robust antitumor activity in pre-clinical models of CDK4/6 inhibitor-naïve and -resistant HR+/HER2- breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-07. |
