Inhibitors of De Novo Guanylate Biosynthesis Enhance the Potency of MAPK Cascade Inhibitors Against Colorectal Cancer.

Despite continuing improvement in the standard of care, the clinical outcomes in metastatic colorectal cancer (CRC) remain poor, especially among patients whose tumors carry activating mutations in BRAF or RAS-family oncogenes. These mutations initiate a series of oncogenic signal transduction events, known as the mitogen-activated protein kinase (MAPK) cascade. While therapeutic targeting of this pathway achieved impressive results in other malignancies, the effectiveness of this approach remains low in CRC. In the current study, we observed that inhibitors of GTP production synergize with various inhibitors of the MAPK cascade in suppressing a variety of CRC cell lines. Furthermore, we discovered that an inhibitor of guanylate biosynthesis increases the efficacy of MAPK cascade inhibitors against human CRC grown in mice. Moreover, a combination of MEK and guanylate biosynthesis inhibitors is more potent than the MEK inhibitor alone in increasing the efficacy of immune therapy in an immunocompetent mouse model. Considering that guanylate biosynthesis inhibitors are already used in clinical practice for other applications, their use in synergistic combinations with the inhibitors of the MAPK cascade may present an actionable strategy to increase the efficacy of the latter.