PKCζ regulates autophagy in pancreatic ductal adenocarcinoma via BAG3: a novel therapeutic vulnerability.

Over the past four decades, efforts to improve the prognosis of pancreatic cancer have yielded limited progress, largely due to the complex genetic mutations, a desmoplastic tumor microenvironment, and the rapid metabolic rewiring that enables pancreatic cancer cells to adapt to cellular stress. Recent studies have demonstrated the critical reliance of pancreatic cancer cells on autophagy for survival, fitness, and the development of resistance to various clinical therapies. These findings position autophagy as a potential therapeutic vulnerability for the development of novel neoadjuvant treatments. However, conventional autophagy inhibition often leads to the accumulation of p62, which activates p62-dependent pathways that promote tumor growth and metastasis, thereby limiting the efficacy of autophagy-targeting therapies. In this study, we demonstrate that the atypical protein kinase C isoform zeta (PKCζ) plays a pivotal role in maintaining intracellular homeostasis in pancreatic ductal adenocarcinoma (PDAC) cells. Inhibition of PKCζ downregulates BCL-2-associated athanogene 3 (BAG3), reduces the expression of key autophagy-related proteins, autophagy related 5 (ATG5) and Beclin-1, and attenuates autophagic flux. Notably, PKCζ-mediated autophagy suppression does not result in p62 accumulation, circumventing the pro-tumorigenic effects associated with conventional autophagy inhibition. Furthermore, PKCζ inhibition enhances the anti-tumor efficacy of other chemotherapeutic agents, such as mitogen-activated protein kinase kinase (MEK) inhibitors, in PDAC. These findings identify PKCζ as a promising therapeutic target and provide a foundation for the development of innovative treatment strategies for pancreatic cancer.