Recruitment of BAG2 to DNAJ-PKAc scaffolds promotes cell survival and resistance to drug-induced apoptosis in fibrolamellar carcinoma

• DOI: 10.1016/j.celrep.2024.113678
• Publication Date: 2024-01-17T22:06:23Z
• Authors: Sophia M. Lauer; Mitchell H. Omar; Martin G. Golkowski; Heidi L. Kenerson; Kyung-Soon Lee; Bryan C. Pascual; Huat C. Lim; Katherine Forbush; F. Donelson Smith; John D. Gordan; Shao-En Ong; Raymond S. Yeung; John D. Scott
• Keywords: Cell Survival

The DNAJ-PKAc fusion kinase is a defining feature of fibrolamellar carcinoma (FLC). FLC tumors are notoriously resistant to standard chemotherapies, with aberrant activity assumed be contributing factor. By combining proximity proteomics, biochemical analyses, and live-cell photoactivation microscopy, we demonstrate that not constrained by A-kinase anchoring proteins. Consequently, the phosphorylates unique array substrates, including proteins involved in translation anti-apoptotic factor Bcl-2-associated athanogene 2 (BAG2), co-chaperone recruited through association Hsp70. Tissue samples from patients exhibit increased levels BAG2 primary metastatic tumors. Furthermore, drug studies implicate DNAJ-PKAc/Hsp70/BAG2 axis potentiating chemotherapeutic resistance. We find Bcl-2 inhibitor navitoclax enhances sensitivity etoposide-induced apoptosis cells expressing DNAJ-PKAc. Thus, our work indicates as marker for advanced resistance signaling scaffolds.