Figure 1. Inhibitors that target MAPK signaling will increase PD-L1 and alter the tumor microenvironment in PDAC.

A. KRAS plays a central role in tumor development, regulating downstream proteins (RAF, MEK, and ERK) that are involved in proliferation, survival, metastasis, and angiogenesis. Oncogenic KRAS induces secretion of molecules that affect surrounding components of the stroma, such as fibroblasts, along with innate and adaptive immune cells. These cells within the tumor microenvironment promote cancer malignancy and provide opportunities for druggable targets in order to facilitate combination therapy strategies. Transferrin receptor (TfR) is a downstream readout for MEK and ERK inhibition. B. Proposed model of how MAPK-targeted therapy (ERK inhibitor SCH772984: abbreviated SCH, and MEK inhibitor trametinib) will alter the tumor microenvironment by activating the immune system and breaking down the stromal components, resulting in a release of cytokines and growth factors, along with a migration of inflammatory cells and macrophages. We also expect there to be an infiltration of immune cells when combined with ICB, and mechanistic studies will determine if and how they are functional.