Direct targeting of oncogenic RAS mutants with a tumor-specific cytosol-penetrating antibody inhibits RAS mutant-driven tumor growth.

ABSTRACT: Oncogenic RAS mutant (RAS^MUT) proteins have been considered undruggable via conventional antibody regimens owing to the intracellular location restricting conventional-antibody accessibility. Here, we report a pan-RAS-targeting IgG antibody, inRas37, which directly targets the intracellularly activated form of various RAS^MUT subtypes after tumor cell-specific internalization into the cytosol to block the interactions with effector proteins, thereby suppressing the downstream signaling. Systemic administration of inRas37 exerted a potent antitumor activity in a subset of RAS^MUT tumor xenografts in mice, but little efficacy in RAS^MUT tumors with concurrent downstream PI3K mutations, which were overcome by combination with a PI3K inhibitor. The YAP1

SUBMITTER: Shin SM 

PROVIDER: S-EPMC6962039 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature