Abstract PO3-29-01: Defining the molecular-genetic mechanism of CDK4/6 inhibition therapy induced senescence to identify biomarkers and determine how senescence contributes to patient outcomes

Abstract In the context of ER+ breast cancers the CDK4/6i have had extraordinary success extending the duration of median PFS, and in some cases, OS, particularly in combination with hormone antagonists.Still there are several individuals who do not have good clinical responses or can only maintain these for a short period of time and then resistance manifests.One challenge to improving patient outcomes by combining CDK4/6i with other modalities is our incomplete understanding of how they induce these beneficial outcomes at the cellular and molecular level.For example, while a few mutations associated with resistance prevent induction of cell cycle exit by the drug, simply inducing cell cycle exit does not explain the positive activity of CDK4/6i. Additional mechanisms such as drug induced enhancement of MHC class I antigen presentation on the surface of treated cancer cells to non-cancer cell autonomous effects on the development of Tregs may also contribute.CDK4/6i can also induce cellular senescence in cancer cell lines in vitro and in mouse models of cancer.Senescence is a cell fate transformation whereby the cell ‘differentiates’ into a stably-arrested, inflammation-provoking cell fate through a largely poorly understood developmental pathway. However, identification of stably arrested and inflammation provoking cells, particularly in human biopsies, has been a pernicious challenge.This might be overcome by identifying the molecular and genetic basis of how senescent cells arise from non-cycling quiescent cells, and two developmental studies, one, carried out in dedifferentiated liposarcoma cell lines treated with CDK4/6i and another during DNA damage induced senescence in primary fibroblasts have begun to do this.These showed that the canonical markers used in the laboratory, such as the accumulation of the CDK inhibitor p16Ink4a or the accumulation of senescence associated beta-galactosidase positive cells, arise well before cells underwent stable arrest.Furthermore, it is now universally acknowledged that the idiotypic heterogeneous nature of the expression of the various cytokines and growth factors that are part of the senescence-associated secretory program, precludes the use of transcripts and proteins culled from lists of gene products associated with senescence in other systems.Thus, the limited analysis of therapy induced senescence in breast cancer cell lines has prevented the evaluation of how this biology, induced by CDK4/6i, might contribute to disease management. We had pioneered the approach to identify late-appearing necessary regulators that control the fate transition from reversible to stable arrest in dedifferentiated liposarcoma. This insight was then used to identify senescent cells in patients and address the contribution that senescence makes over time. In this presentation we will describe similar but as of yet unpublished work describing the detailed temporal molecular genetic analysis of CDK4/6i therapy induced senescence in ER+ breast cancer cell lines, and discuss how we have nominated highly specific late markers of cellular senescence for application in a number of archival and ongoing clinical trials to determine (1) whether therapy induced senescence contributes to disease management and (2) how its contributions change over time.Such insights will further inform patient care and also drive research in model organisms to unravel the complex role that senescence plays in breast cancer development and therapy. Citation Format: Marimar Benitez, Rei Kudo, Caroline Gleason, Sarat Chandarlapaty, Andrew Koff. Defining the molecular-genetic mechanism of CDK4/6 inhibition therapy induced senescence to identify biomarkers and determine how senescence contributes to patient outcomes abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-29-01.