Peter Y. Yu

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy and has long been regarded as a therapeutic “drug graveyard,” with modest gains from cytotoxic combination chemotherapy and numerous novel agents failing to show benefit in clinical trials. The quest to directly target RAS has moved from concept to reality with the Food and Drug Administration (FDA) approval of daraxonrasib (Rasonque) for adults with metastatic PDAC who have received at least one prior systemic therapy or are not candidates for multiagent systemic therapy. In this review, we discuss a wave of clinical trials that are poised to change this narrative and usher in the era of RAS-targeted therapy. Given the flood of compounds and combinations, we focus on therapies that have advanced to phase III clinical trials. Collectively, these studies demonstrate how RAS-targeted therapies are poised to transform the PDAC treatment landscape. The current generation of trials will determine whether these emerging strategies can translate into durable survival gains and turn PDAC from a “drug graveyard” into a drug haven for novel therapies.

Higher density of CXCR2 positive macrophages was observed in autophagy-inhibited PDAC tumors compared to the control tumors.

Pancreatic ductal adenocarcinoma (PDAC) relies on elevated autophagy to support metabolism, proliferation, and immune evasion. Inhibiting autophagy has been reported to improve response rates in patients with PDAC. In this work, we identified a mechanism to explain how the loss of autophagy in PDAC triggers reprogramming of the tumor microenvironment (TME) to ultimately stimulate an antitumor response. Autophagy inhibition in PDAC recruited macrophages via the CXCL1/2-CXCR2 axis. Simultaneously, the loss of autophagy resulted in a decrease in the canonical “don’t eat me” ligand CD47 on tumor cells, thereby inducing their susceptibility to macrophage phagocytosis. Although CD8+ T cells were critical to the antitumor immune response to autophagy inhibition in PDAC, they were not directly involved in cytotoxicity but played a critical role in stimulating macrophage phagocytosis of tumor cells. Taken together, this study strongly supports the implementation of autophagy inhibition in pancreatic cancer and highlights a crucial link between PDAC biology and the TME-macrophage cross-talk that effectively promotes tumor cell killing. Significance:Inhibition of autophagy in pancreatic cancer promotes antitumor immunity through a stepwise process of recruiting macrophages and enhancing phagocytosis of cancer cells, providing a potential therapeutic strategy for this deadly tumor type.

Autophagy inhibition in PDAC cells suppressed the growth of orthotopic implanted tumors and promoted macrophage and CD8+ T cell infiltration

Timelapse videos of macrophage phagocytosis in the cocultures with control (mST) or autophagy-inhibited PDAC cells (4B).

Timelapse videos of macrophage phagocytosis in the cocultures with control (mST) or autophagy-inhibited PDAC cells (4B).

Macrophages killed autophagy-inhibited PDAC cells in coculture and phagocytosed multiple tumor cells in autophagy-inhibited PDAC tumors.

Timelapse videos of macrophage phagocytosis in the cocultures with control (mST) or autophagy-inhibited PDAC cells (4B).

ATG4BC74A expression in PDAC cells promoted the upregulation of P62 and LC3B-I in tumor cells.