Silent mutations reveal therapeutic vulnerability in RAS Q61 cancers

Yoshihisa Kobayashi (), Chhayheng Chhoeu, Jiaqi Li, Kristin S. Price, Lesli A. Kiedrowski, Jamie L. Hutchins, Aaron I. Hardin, Zihan Wei, Fangxin Hong, Magda Bahcall, Prafulla C. Gokhale and Pasi A. Jänne ()
Additional contact information
Yoshihisa Kobayashi: Dana-Farber Cancer Institute
Chhayheng Chhoeu: Dana-Farber Cancer Institute
Jiaqi Li: Dana-Farber Cancer Institute
Kristin S. Price: Guardant Health
Lesli A. Kiedrowski: Guardant Health
Jamie L. Hutchins: Guardant Health
Aaron I. Hardin: Guardant Health
Zihan Wei: Dana-Farber Cancer Institute
Fangxin Hong: Dana-Farber Cancer Institute
Magda Bahcall: Dana-Farber Cancer Institute
Prafulla C. Gokhale: Dana-Farber Cancer Institute
Pasi A. Jänne: Dana-Farber Cancer Institute

Nature, 2022, vol. 603, issue 7900, 335-342

Abstract: Abstract RAS family members are the most frequently mutated oncogenes in human cancers. Although KRAS(G12C)-specific inhibitors show clinical activity in patients with cancer1–3, there are no direct inhibitors of NRAS, HRAS or non-G12C KRAS variants. Here we uncover the requirement of the silent KRASG60G mutation for cells to produce a functional KRAS(Q61K). In the absence of this G60G mutation in KRASQ61K, a cryptic splice donor site is formed, promoting alternative splicing and premature protein termination. A G60G silent mutation eliminates the splice donor site, yielding a functional KRAS(Q61K) variant. We detected a concordance of KRASQ61K and a G60G/A59A silent mutation in three independent pan-cancer cohorts. The region around RAS Q61 is enriched in exonic splicing enhancer (ESE) motifs and we designed mutant-specific oligonucleotides to interfere with ESE-mediated splicing, rendering the RAS(Q61) protein non-functional in a mutant-selective manner. The induction of aberrant splicing by antisense oligonucleotides demonstrated therapeutic effects in vitro and in vivo. By studying the splicing necessary for a functional KRAS(Q61K), we uncover a mutant-selective treatment strategy for RASQ61 cancer and expose a mutant-specific vulnerability, which could potentially be exploited for therapy in other genetic contexts.

Date: 2022
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DOI: 10.1038/s41586-022-04451-4

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