Abstract 5722: Preclinical activity of CDK4/6 inhibitor alone or in sequential combination with chemotherapy using breast cancer cell line-derived organoid culture
Authors: Kamita Moses , Ali Haythem , Jiagge Evelyn , Bensenhaver Jessica , Walker Eleanor 
Published: March 2024

Abstract
Breast cancer ranks as the most prevalent cancer globally, with lung and colorectal cancers following closely. Dysregulation of the cyclinD:CDK4/6:Rb axis has been shown to be a common feature in a number of human malignancies, including breast cancer. Targeting this pathway has emerged as a promising strategy for breast cancer treatment. Currently, the U.S. Food and Drug Administration has approved three CDK4/6 inhibitors for advanced hormone receptor-positive, HER2-negative breast cancer, when used in combination with endocrine therapy. However, there are still many breast cancer cases that do not qualify for these criteria and, therefore, do not benefit from CDK4/6 inhibitors prompting investigations into their potential synergy between CDK4/6 inhibitors with chemotherapy. Efforts are currently being made to test the application of these drugs in combination with chemotherapy. Previous studies have demonstrated a synergetic effect of combining CDK4/6 inhibitors and other therapies to treat breast and prostate cancers. While many studies administer these drugs concurrently, our hypothesis proposes a sequential combination approach. This method involves arresting cell cycle at the G0G1 phase using CDK 4/6 inhibitors and then releasing the drug when the cells are more vulnerable to chemotherapy treatment. Such an approach has the potential to expand the application of CDK4/6 inhibitors beyond ER+/HER2- breast cancer. The primary objective of this study is to evaluate the effectiveness of CDK4/6 inhibitors, both alone and in sequential combination with chemotherapy, across a range of breast cancer subtypes. Breast cancer cell lines (MDA-MB-231, HCC70 and T47D) were used in the study. For each cell line, a total of 3x105 cells were seeded in a 6-well plate, and after an overnight incubation, the media was changed with or without a CDK4/6 inhibitor (abemaciclib) and cultured for up to 72 hours. We monitored the drug's efficacy through flow cytometry and cell counting. Abemaciclib suppressed cell proliferation and cell cycle in G0G1 phase in the treated cells compared with the control. The results were similar in both receptor-positive and triple-negative breast cancer cell lines. The effect of abemaciclib was dose-dependent, and reversible at least 48 hours after drug withdrawal, suggesting an opportune time for administering chemotherapy. Future research will delve into investigating the efficacy of sequential treatment with chemotherapy after CDK 4/6 inhibitor withdrawal, utilizing 2D and 3D culture systems.
Citation Format: Moses Kamita, Haythem Ali, Evelyn Jiagge, Jessica Bensenhaver, Eleanor Walker. Preclinical activity of CDK4/6 inhibitor alone or in sequential combination with chemotherapy using breast cancer cell line-derived organoid culture [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5722.