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Inhibition of K-RAS effectors like B-RAF or MEK1/2 is accompanied by treatment resistance in cancer patients via re-activation of PI3K and Wnt signaling. We hypothesized that myotubularin-related-protein-7 (MTMR7), which inhibits PI3K and ERK1/2 signaling downstream of RAS, directly targets RAS and thereby prevents resistance. Using cell and structural biology combined with animal studies, we show that MTMR7 binds and inhibits RAS at cellular membranes. Overexpression of MTMR7 reduced RAS GTPase activities and protein levels, ERK1/2 phosphorylation, c- FOS transcription and cancer cell proliferation in vitro. We located the RAS-inhibitory activity of MTMR7 to its charged coiled coil (CC) region and demonstrate direct interaction with the gastrointestinal cancer-relevant K-RASG12V mutant, favouring its GDP-bound state. In mouse models of gastric and intestinal cancer, a cell-permeable MTMR7-CC mimicry peptide decreased tumour growth, Ki67 proliferation index and ERK1/2 nuclear positivity. Thus, MTMR7 mimicry peptide(s) could provide a novel strategy for targeting mutant K-RAS in cancers. • RAS mutations underlie resistance of gastrointestinal cancers to clinical therapies. • We identified the lipid phosphatase MTMR7 as a novel physiological inhibitor of mutant RAS. • MTMR7 peptide derived from its coiled coil domain stabilized the inactive form of GDP bound K-RAS G12V. • Cell permeable MTRM7-derived peptide mitigated growth of gastric and colorectal cancer in mice. • We may develop new treatments based on the MTMR7-derived peptide for patients with RAS mutant cancers. [ABSTRACT FROM AUTHOR]