RAF/MEK dependence of KRAS-mutant pancreatic ductal adenocarcinomas

Abstract

Studies using genetically engineered mouse models indicate that RAF activation is sufficient to induce pancreatic intraepithelial neoplasms, suggesting that mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor-based combination approaches may have clinical use in patients with pancreatic ductal adenocarcinomas.

Figure 1. Targeting RAS effectors in pancreatic ductal adenocarcinoma (PDA

Mutational activation of KRAS is found in >90% of PDA and contributes to tumor initiation and progression of the disease. PDA is almost universally fatal due to late-stage at diagnosis and intrinsic resistance to conventional chemotherapy and radiation. Data from Collisson and colleagues suggests that activation of BRAF (highlighted in red) is sufficient to recapitulate the tumor initiation and progression seen with activated KRAS in mouse and human PDA. These data imply that targeting RAF/MEK/ERK signaling downstream of KRAS may be of clinical utility in PDA. Treatment with MEK inhibitors is associated with a reciprocal increase in AKT activity and MEK inhibitor based combinatorial approaches will be needed to induce durable tumor regressions. Selective inhibitors of RAF (Vemurafinib, Dabrafenib) and MEK (Trametinib) kinases have recently been shown to prolong survival in patients with BRAFV600E mutant melanomas. Selective inhibitors of RAF induce a paradoxical activation of ERK signaling in KRAS mutant tumors whereas MEK inhibitors downregulate ERK pathway activity irrespective of tumor genotype.