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

Abstract:

: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 the intracellularly activated form of various RASMUT 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 RASMUT tumor xenografts in mice, but little efficacy in RASMUT tumors with concurrent downstream PI3K mutations, which were overcome by combination with a PI3K inhibitor. The YAP1 protein was up-regulated as an adaptive resistance-inducing response to inRas37 in RASMUT-dependent colorectal tumors; accordingly, a combination of inRas37 with a YAP1 inhibitor manifested synergistic antitumor effects in vitro and in vivo. Our study offers a promising pan-RAS-targeting antibody and the corresponding therapeutic strategy against RASMUT tumors.

journal_name

Sci Adv

journal_title

Science advances

authors

Shin SM,Kim JS,Park SW,Jun SY,Kweon HJ,Choi DK,Lee D,Cho YB,Kim YS

doi

10.1126/sciadv.aay2174

subject

Has Abstract

pub_date

2020-01-15 00:00:00

pages

eaay2174

issue

3

issn

2375-2548

pii

aay2174

journal_volume

6

pub_type

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