FADD: A Mechanistic Basis and Therapeutic Opportunity for Overcoming CDK4/6 Inhibitor Resistance
Abstract
Endocrine therapy has been used for the treatment of estrogen receptor-positive (ER+) breast cancer for many years. However, the development of resistance to this therapy led to the inclusion of inhibitors of the CDK4/6 kinases, including palbociclib, ribociclib, and abemaciclib, in combination with endocrine therapy for women with ER+ breast cancer. This combination therapy has demonstrated significantly improved survival compared to endocrine therapy alone in ER+ advanced breast cancer, resulting in the approval of CDK4/6i with endocrine therapy in the first-line setting. However, some patients have tumors that do not respond to CDK4/6i, and a significant number of patients with tumors that initially respond to these drugs will succumb to disease due to the development of resistance, underscoring the need to new approaches to block the growth of tumors cells. Our team has identified a novel signaling pathway that bypasses CDK4/6 inhibitors. Our preliminary findings show that FADD protein, when phosphorylated, can overcome CDK4/6 inhibitor effectiveness and promote the growth of cancer cells. We believe that Casein Kinase 1a (CK1a) plays a critical role in this resistance and the CDK 4/6 inhibitor resistance can be overcome with CK1a inhibition. Importantly, drugs that inhibit the protein that phosphorylates FADD, CK1a, have been approved for the treatment of patients with myelodysplastic syndrome (MDS), and additional improved drugs targeting CK1a are being tested in patients. The studies proposed in this grant application will investigate the safety, efficacy, and mechanism by which CK1a inhibitors can prevent the development of resistance to endocrine therapy and CDK4/6 inhibitors. If successful, these studies will provide improved survival for breast cancer patients in the Armed Forces and the general public.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310210
Entities
People
- Alnawaz Rehemtulla
Organizations
- United States Army
- University of Michigan