Role of p73-mediated DR5 induction in therapeutic response to CDK inhibition.

/ABSTRACT Targeting cyclin-dependent kinases (CDKs) has recently emerged as a promising therapeutic approach against cancer. Small-molecule CDK4/6 inhibitors have been approved for the treatment of a subset of breast cancer and shown promising activity against other cancers including colorectal cancer (CRC), a leading cause of cancer-related deaths in the United States. A variety of other CDK inhibitors have been developed and are currently being evaluated in ongoing clinical studies. The next generation of highly selective CDK inhibitors holds great promise for improving the clinical utility of CDK-targeted therapies. However, the anticancer mechanisms of CDK inhibitors, especially newly developed selective inhibitors, remain poorly understood. Emerging evidence suggests that inhibition of non-canonical functions of CDKs contributes to tumor suppression by CDK inhibitors. Our recent studies revealed that CDK inhibition leads to dephosphorylation and nuclear translocation of the p53 family member p73, which transcriptionally activates death receptor 5 (DR5), a cytokine receptor and key regulator of apoptosis. Deletion of DR5 or p73 in CRC cells abrogated the in vitro and in vivo therapeutic effects of CDK4/6 inhibitors in combination with other anticancer agents, including 5-fluorouracil (5-FU) and anti-PD-1 antibody that are widely used for treating CRC patients. Based on these findings, we propose to test the hypothesis that p73-mediated DR5 induction promotes therapeutic response to selective CDK inhibition in CRC via both cell-intrinsic and immunologic effects. Aim 1. Mechanism and functional role of p73-mediated DR5 induction upon CDK perturbation. Aim 2. Functional role of p73-mediated DR5 induction in therapeutic response to selective CDK inhibition. Aim 3. Immunogenic effects of p73-mediated DR5 induction in response to selective CDK inhibition. We will use mouse tumor models because they closely mirror human tumor biology and treatment response, providing the most appropriate in vivo systems for the proposed experiments. The proposed studies will provide new mechanistic insights for understanding the anticancer mechanisms of next-generation selective CDK inhibitors. These studies will also develop rationales and potential biomarkers for effective combinations of CDK inhibitors with other anticancer agents, which may lead to improved therapies against CRC and other cancers. Project Number: 1R01CA311678-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Lin Zhang | Institution: UNIVERSITY OF SOUTHERN CALIFORNIA, Los Angeles, CA | Award Amount: $560,863 | Activity Code: R01 | Study Section: Mechanisms of Cancer Therapeutics C Study Section [MCTC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11343650