Abstract SY22-02: Cell cycle plasticity drives tumor progression and drug resistance

Abstract The cancer cell cycle possesses an incredible capacity to adapt or change in response to oncogenic mutations or drug treatment (cell cycle “plasticity”) to generate a diversity of solutions to the cell cycle (distinct cell cycle “programs”) that differ in key regulatory effectors and mechanisms. To study the extent and role of cell cycle plasticity in tumor progression and drug resistance, we developed cell cycle mapping - a single-cell proteomic imaging platform that combines highly multiplexed immunofluorescence with manifold learning to visualize cell cycle plasticity among and within tumors. Applying cell cycle mapping to a large library of hormone receptor (HR)+ breast tumors, we observed 4 distinct cell cycle programs driving tumor growth. These programs differed in the expression/activity of key cyclins and CDKs. In many cases, we observed multiple cell cycle programs within a single tumor correlating with differences in the cellular composition of the local tumor environment. These results also highlight the challenge of targeting the cancer cell cycle (e.g. with CDK4/6 inhibitors), given the heterogeneity of cell cycle programs actin within a single tumor. To further explore the role of cell cycle plasticity in targeted therapy, we used a combination of cell cycle mapping and time-lapse imaging to reveal how the breast cancer cell cycle responds to a panel of FDA-approved drugs targeting a range of cell cycle effectors, including multiple CDK inhibitors. We observed clear heterogeneity in the mechanisms of cell cycle adaptation executed across a panel of cell lines modeling distinct molecular (HR+, HER2+, basal) and histological subtypes (invasive ductal carcinoma, invasive lobular carcinoma) of breast cancer. Altered expression/activity of key cell cycle regulators provides a new “path” through the cell cycle, a molecular detour that allows cells to continue proliferating in the presence of drug to drive therapeutic resistance. Citation Format: Yian Yang, Thu Pham, Janet McLaughlin, Steffi Oesterreich, Adrian Lee, Katarzyna Kedziora, Wayne Stallaert. Cell cycle plasticity drives tumor progression and drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY22-02.