Abstract 2449: p38β promotes cancer stemness and chemoresistance in hepatocellular carcinoma

Abstract

Abstract Protein kinases control a variety of oncogenic functions through a phosphotransfer dependent signal transduction cascade in cancers where potent and selective inhibitors could be developed with favorable pharmaceutical properties. In hepatocellular carcinoma (HCC), increasing evidence suggested that cancer stemness is a driving force of therapy resistance which is tightly controlled by kinase-dependent signaling cascades. However, there are still limited druggable kinase targets that are developed to combat cancer stemness and therapy resistance for HCC treatment. To identify potential kinase targets which promote stemness, survival and therapy resistance in HCC, two datasets profiling kinase genes which are important for HCC survival and chemoresistance in HCC spheres were compared. p38 MAPK beta (p38β) was found to be a common top-ranked kinase important for these functions. Clinically, biopsies of human HCC showed high expression of total and activated forms of p38β, suggesting that p38β could be a potential therapeutic target in HCC. Functionally, we demonstrated that p38β promoted HCC tumor initiation, self-renewal and resistance towards chemotherapy by cisplatin. Using tandem affinity purification coupled with mass spectrometry, we identified BiP, which is a chaperone protein, as a novel binding partner of p38β. Subsequent mechanistic validation and mass spectrometry analysis showed that p38β directly phosphorylates BiP at a previously unrecognized phosphorylation site. Rescue experiments with BiP mutation and inhibition abrogated the stemness and chemoresistant properties observed in p38β overexpressing HCC cells. Taken together, we identified and characterized p38β and its direct phosphorylation target BiP as critical regulators for promoting cancer stemness and chemoresistance in HCC. Citation Format: Ianto Bosheng Huang, Yunong Xie, Tin Lok Wong, Terence Kin Wah Lee, Jing-Ping Yun, Stephanie Kwai Yee Ma, Man Tong. p38β promotes cancer stemness and chemoresistance in hepatocellular carcinoma [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 2449.