Molecular and clinical characterization of sensivity to SHP2 inhibition in KRAS-mutant cancers

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K23909
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Kano Yoshihito 東京医科歯科大学, 大学院医歯学総合研究科, 講師 (10633125)
• Project Period (FY): 2019-08-30 – 2022-03-31
• Keywords: KRAS / SHP2阻害 / Q61変異 / クリニカルシークエンス

Outline of Final Research Achievements

KRAS mutations are found in some of the most aggressive and deadly cancers, including up to 25% of lung cancers to and over 90% of pancreatic cancers. A recent series of reports suggest that SHP2 inhibition (SHP2i) is effective to KRAS-mutated cancers including non-small cell lung and pancreatic cancers. Here, we report that lung and pancreatic cancer cells that harbor KRAS Q61H mutation are uniquely resistant to SHP2i. Our biochemical studies show that the Q61H mutation has negligible impact on binding to BRAF-RBD. Whereas phosphorylation of WT and G12 mutants impairs binding to BRAF-RBD, the uncompromised ability of phosphorylated KRAS Q61H to activate MAPK signaling is retained. The independence of KRAS Q61H from the stimulatory roles of SHP2 in reversing Src phosphorylation confers resistance to SHP2i. Together these insights provide an unprecedented mechanistic understanding of oncogenic KRAS mutants that can guide clinical trials of SHP2i for cancer patients bearing KRAS Q61H.

Free Research Field

臨床腫瘍学

Academic Significance and Societal Importance of the Research Achievements

SHP2は脱リン酸化酵素として初のがん遺伝子であり、機序は不明ながらKRASシグナルに深く関与する一方で、KRASと同様に長らくundruggable targetと考えられていた。しかし近年SHP2に対する低用量かつ経口投与可能な薬剤が開発されている。今回申請者はKRASとSHP2を直接関連づけるメカニズムとしてKRASリン酸化モデルを提唱した。さらに特定の変異型に対するSHP2阻害の感受性の違いを明らかとした。SHP2阻害剤は現在Phase I試験中であるがKRAS変異型による感受性の差を考慮した臨床試験のデザインが必要であり、今後への提言としたい。