2025 Theses Doctoral

Expanding and potentiating the role of CDK4/6 inhibitors in breast cancer treatment

Armand, Jessica

FDA approval of CDK4/6 inhibitors (CDK4/6i) palbociclib, ribociclib, and abemaciclib in combination with endocrine therapy (ET) has revolutionized the first-line treatment landscape for metastatic Hormone Receptor positive, Human Epidermal Growth Factor 2 negative (HR+/HER2-) breast cancer. This regimen of combination targeted therapies has improved progression free survival (PFS) with well tolerated safety profiles. As such, its clinical administration is preferred over that of harsh systemic chemotherapies in approved populations. However, the emergence of resistance is common, and there is a lack of reliable biomarkers to predict patient response. Disease progression has limited the long-term efficacy of CDK4/6i in breast cancer treatment, and there is a lack of consensus second line treatment options.

The ultimate purpose of this dissertation is to potentiate the role of CDK4/6i in its current indications and expand its efficacy to triple negative breast cancer. More specifically, we aim to understand 1) mechanisms of CDK4/6i resistant cell proliferation, 2) whether continued treatment of CDK4/6i can offer therapeutic benefit after disease progression, and 3) methods to sensitize TNBC models to targeted CDK4/6i therapy.

This work uses an innovative combination of genetic engineering, high throughput single cell imaging, in vitro/in vivo modeling, clinical data, and next generation sequencing to answer the aforementioned questions. The development of breast cancer tumor cell lines expressing kinase translocation reporters (KTRs) and cell cycle phase sensors allowed for the real time monitoring of heterogeneous response to drug treatment to investigate the differences in cellular decision making that dictate drug response. Mechanisms identified in vitro were then escalated and recapitulated in mouse models, as well as human tissue samples where appropriate. Unbiased chemogenomic screens, genetic manipulation and next generation sequencing were also employed to identify candidate drivers of resistance, and confirm their effect on phenotype, transcriptional profiles, and chromatin accessibility.

These efforts are separated into three chapters in which we 1) define mechanisms of drug resistance and identify c-Myc protein as a pre-treatment biomarker of CDK4/6i efficacy, 2) measure continued therapeutic benefit of CDK4/6i plus ET administration and addition of CDK2 inhibitors (CDK2i) after disease progression and 3) highlight mechanisms of TNBC CDK4/6i persister development to propose combination therapies that can improve potency in TNBC. Taken together, this work serves as a compelling investigation of CDK4/6i resistance in the treatment of breast cancer.