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

• DOI: 10.1126/sciadv.aay2174
• Publication Date: 2020-01-16T00:15:22Z
• Authors: Seung-Min Shin; Ji-Sun Kim; Seong-Wook Park; Sei-Yong Jun; Hye-Jin Kweon; Dong-Ki Choi; Dakeun Lee; Yong Beom Cho; Yong-Sung Kim
• Keywords: 0301 basic medicine; Dose-Response Relationship, Drug; Endosomes; Integrin alphaVbeta3; Xenograft Model Antitumor Assays; Endocytosis; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; Antineoplastic Agents, Immunological; Immunoglobulin G; Neoplasms; Mutation; ras Proteins; Animals; Humans; Research Articles; Cell Proliferation; Signal Transduction

Oncogenic RAS mutant (RASMUT) 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 intracellularly activated form of various RASMUT subtypes after tumor cell-specific internalization into cytosol block interactions with effector proteins, thereby suppressing downstream signaling. Systemic administration inRas37 exerted potent antitumor activity in subset xenografts mice, but little efficacy tumors concurrent PI3K mutations, were overcome by combination inhibitor. The YAP1 protein was up-regulated as an adaptive resistance-inducing response RASMUT-dependent colorectal tumors; accordingly, inhibitor manifested synergistic effects vitro and vivo. Our study offers promising corresponding therapeutic strategy against tumors.