Targeting Autophagy in RAS Mutant Cancers: Exploring the Potential of DCC-3116 as a Therapeutic Agent

Cancer cells often trigger autophagy to endure harsh conditions and chemotherapy, with RAS mutation cancers relying heavily on this process for growth. Traditional MAPK pathway inhibitors have failed to treat these cancers due to their tendency to boost autophagy. A novel strategy involves combining MAPK inhibitors with autophagy blockers, as demonstrated with chloroquine derivatives in cancer models and a RAS mutation patient. However, chloroquine's broad impact on lysosomal function and tissue accumulation, particularly in the brain, calls for a more targeted approach. The ULK1/2 kinases, initiators of autophagy, offer a promising target. DCC-3116, an ULK inhibitor, has been developed and evaluated for its potential in treating RAS mutation cancers.

In vitro assays and cell tests were conducted using ATP and a peptide substrate to measure kinase activity and autophagy-related processes. The compound was found to be a potent and selective inhibitor of ULK1/2, with minimal off-target effects. It effectively reduced phosphorylation of ATG13, hindered autophagosome formation, and showed a synergistic effect with MAPK inhibitors in inhibiting cancer cell growth. In vivo studies using xenograft models demonstrated sustained inhibition of ATG13 phosphorylation following oral administration and enhanced tumor growth inhibition when combined with MAPK inhibitors. Notably, DCC-3116 showed low brain penetration, suggesting minimal impact on CNS autophagy.

The findings indicate that the targeted inhibition of autophagy through ULK kinases, in conjunction with MAPK pathway inhibitors, could be a valuable therapeutic strategy for RAS mutation cancers. DCC-3116 has shown promise as an autophagy inhibitor and is a candidate for further development in treating these cancers.