Abstract 5791: Autophagy & PIM1 kinase inhibition in breast cancer stem cells & bulk cancer cells attenuates breast cancer & metastasis

Abstract

Abstract Autophagy is a self-degradation process, it is essential for growth of heterogenous of breast cancer cells. Breast tumor heterogeneity majorly comprises bulk cancer cells & cancer stem cells (CSCs). Targeting either CSCs or cancer cells could lead to interconversion between these cells due to EMT/MET transitions. Therefore, it is important to identify a common molecular targets & its mechanism of regulation in these populations for improvement of breast cancer therapy. Here, we utilized a PCR based screen & identified NUMA1 downregulation in FIP200 KO (autophagy gene) cells of three major breast cancer subtypes, FF99 (luminal), N418 (Her2+) & BF3M (basal). Further, NUMA1 KO in these cells reduced tumor formation & CSCs indicating the role of NUMA1 on regulation of CSCs. Therefore, we sorted breast CSCs, ALDH+ and CD29hi CD61+ from WT & NUMA1 KO cells, tail-vein injected nude mice depicted reduced metastatic potential with NUMA1 KO than WT CSCs. Mechanistically, NUMA1 regulation by PIM1 kinase was observed in CSCs but not in bulk cancer cells. Cell viability assays revealed that combination treatment of autophagy & PIM1 inhibitor showed higher efficacy against cancer cells of three breast cancer subtypes than individual treatments alone. Finally, the combination treatment of autophagy inhibitor, Lys05 & PIM1 inhibitor, SMI-4a reduced tumor formation & metastasis of breast cancer. Human tissue microarray results depicted high expression of NUMA1 & PIM1 in different breast cancer subtypes than non- tumor tissues. Our study demonstrated that inhibition of autophagy & PIM1 in bulk cancer cells & CSCs showed attenuation of tumor formation & metastasis, suggesting this combination treatment serves as an important therapeutic approach for treating breast cancer. Citation Format: Kanakaraju Manupati, Mingang Hao, Michael Haas, Syn Kok Yeo, Jun-Lin Guan. Autophagy & PIM1 kinase inhibition in breast cancer stem cells & bulk cancer cells attenuates breast cancer & metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5791.