Discovery of splicing vulnerability and novel therapy in RAS Q61 cancers -Nature-Collaborative Team of Dana-Farber Cancer Institute and National Cancer Center Japan

March 3, 2022
National Cancer Center Japan

in Japanese

Highlights

• An essential role of silent mutations in splicing and production of a functional KRAS Q61K oncogenic protein was uncovered.
• Splicing vulnerabilities that can be exploited therapeutically were identified in KRAS, NRAS and HRAS Q61X mutant cancers.
• A proof of concept was demonstrated that the induction of aberrant splicing in a mutant selective manner using an antisense oligonucleotide approach leads to tumor cell growth inhibition in vitro and in vivo.

Summary

RAS family members are the most frequently mutated oncogenes in human cancers. Although KRAS G12C-specific inhibitors show clinical activity in patients with cancer, there are no direct inhibitors of NRAS, HRAS or non-G12C KRAS variants. New research by the collaborative team of Dr. Pasi A. Jänne from Department of Medical Oncology, Dana-Farber Cancer Institute (Boston, USA) and Dr. Yoshihisa Kobayashi from Division of Molecular Pathology, National Cancer Center Japan (Tokyo, Japan) uncovered the requirement of a silent mutation in KRAS G60G for a functional KRAS Q61K oncogenic protein. The team further reveal that the region around RAS Q61　has splicing vulnerabilities. The induction of aberrant splicing by mutant-selective antisense oligos demonstrated therapeutic effects in vitro and in vivo. By studying a mutant-specific vulnerability in splicing, a novel mutant selective RAS Q61 cancer treatment strategy was uncovered, which could potentially be therapeutically exploited in other genetic contexts.

Publication

Journal name

Nature

Title

Silent mutations reveal therapeutic vulnerability in RAS Q61 cancers

Authors

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, Pasi A. Jänne* *Co-Correspondence

DOI

10.1038/s41586-022-04451-4

URL

https://www.nature.com/articles/s41586-022-04451-4(linked at extenal site)

Publication date

March 2, 2022 (London time)

Enquiries

On Research

Yoshihisa Kobayashi
Division of Molecular Pathology
National Cancer Center Japan
E-mail: yoshikob●ncc.go.jp

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