Abstract P4-01-18: Acquired sensitivity strategies in ER+ breast cancer progressing on CDK4/6 and mTOR inhibitors

Abstract

Abstract Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors and mammalian target of rapamycin (mTOR) inhibitors have become important components of the clinical management of metastatic ER+ breast cancer. Despite the benefit of these treatments, progression and resistance will still develop in the majority of patients. Therefore, it is important to research strategies that can increase response durability and effectiveness of these therapies. The aim of our study is to use the identified acquired resistance targets in progressing patients for treatment approaches. Our previous studies on the evolution of resistance using transcriptomic analysis in earlier stage patients as they progress on therapy identified resistance pathways that include the MAPK, AKT, and survival signaling pathways. We used isogenic breast cancer cell lineages sensitive and resistant to CDK4/6 inhibitors, ribociclib and abemaciclib, and the mTOR inhibitor, everolimus, to determine the efficacy of drug combinations targeting the acquired resistance JNK, MAPK and AKT pathways. The effect of the pathways’ inhibition in the resistant cells was examined in vitro, in 2D drug response assays, and in 3D spheroid assays. Our results indicate increased potency in the resistant cells to the combination therapies with JNK and TIC10/ONC201 inhibitors which are currently seeing promise in clinical trials. These findings were validated in 2D and 3D in vitro studies with patient derived breast cancer cells under the same combination treatments, recapitulating the increased response to combination therapy and further supporting clinical relevance. In conclusion, our study leveraged our patient data cohorts as well as pre-clinical models to identify acquired sensitivity to JNK, MAPK and AKT inhibition. With the linking of both patient derived data with isogenic cell line driven experiments, our study provides validated findings in various settings strengthening the potential of clinical applications of these targetable pathways. Citation Format: Eleni Farmaki, Rena Emond, Patrick Cosgrove, Andrea Bild. Acquired sensitivity strategies in ER+ breast cancer progressing on CDK4/6 and mTOR inhibitors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-01-18.