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 Advjournal_title
Science advancesauthors
Shin SM,Kim JS,Park SW,Jun SY,Kweon HJ,Choi DK,Lee D,Cho YB,Kim YSdoi
10.1126/sciadv.aay2174subject
Has Abstractpub_date
2020-01-15 00:00:00pages
eaay2174issue
3issn
2375-2548pii
aay2174journal_volume
6pub_type
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