Combined MEK, STAT3 and PD-1 Inhibition in Metastatic Pancreatic Ductal Adenocarcinoma

Adenocarcinoma of the pancreas (PDAC) remains a major therapeutic challenge due to its innate and acquired chemoresistance. Three major contributors to therapeutic resistance that have been difficult to overcome in PDAC are mutations in the KRAS oncogene, the presence of a dense desmoplastic stroma that acts as a barrier to drug delivery and effector immune cell infiltration, and the immunosuppressive tumor microenvironment (TME) that renders the tumor innately resistant to immunotherapy. The Merchant and Datta labs at the University of Miami (UM) has extensively studied the targeting of downstream effectors of oncogenic RAS. They have shown that mitogen-activated extracellular signal-regulated kinase inhibition (MEKi) results in reciprocal activation of signal transducer and activator of transcription 3 (STAT3) signaling, which confers therapeutic resistance and continued PDAC cell growth. Combined inhibition of Janus kinases (JAK)/STAT3 (STAT3i) and MEKi overcomes therapeutic resistance following RAS inhibition that is mediated through parallel feedback loop activation. They have also identified a novel mechanism showing that combined MEKi and STAT3i also inhibits tumor fibrosis and enhances CD8+ cytotoxic T-cell (CTL) infiltration to the tumor while downregulating immunosuppressive regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs) in the TME, resulting in reduced tumor burden and improved survival in genetically engineered mouse models of PDAC. Furthermore, they have shown that the anti-tumor effects of MEKi and STAT3i are T-cell dependent. This change in the TME, however, is accompanied by sustained PD-L1/PD-1 and cytotoxic T lymphocyte antigen-4 (CTLA-4) expression. The preliminary results further demonstrate that combined MEKi and STAT3i with PD-1 inhibition can harness the effects of immune checkpoint inhibitors for an enhanced anti-tumor response. Based on many years of preclinical investigation, this triplet combination appears to be a promising option and this clinical trial will tests its safety and effectiveness in patients with metastatic PDAC.