Abstract B031: Inhibition of mutant RAS via myotubularin related protein 7-mimicking peptide

Abstract

Abstract The coiled coil domain of Myotubularin Related Protein 7 (MTMR7) and a peptide of the same sequence (M7CC) have been shown to have an anti-cancer effect via direct interaction with PPARγ (Weidner et al. 2020). The same studies also found an inhibition of ERK-mediated inactivation of PPARγ by the same peptide. In this work we have followed up on our previous findings and show a direct effect on mutant RAS activity, mediated by MTMR7 and M7CC. In the presence of MTMR7 or M7CC, a drop of active RAS-levels along with a delocalization from the plasma membrane can be observed. This goes along with a significant drop in the levels of phosphorylated ERK and the expression of RAS-controlled genes. This led to a decrease of cell proliferation in cell culture in different cancer cell lines and of tumor volume in mouse models. The effect of MTMR7 or M7CC on RAS levels was shown to be mediated by a direct interaction with RAS. Using biophysical studies including solution-state NMR spectroscopy, the interaction was in vitro shown to happen with the globular domain of K-Ras4B. Our results support a model for MTMR7 as part of a novel RAS-regulation machinery, and highlights MTMR7 as promising scaffold to be exploited for peptide-based cancer treatment.