The Q61H mutation decouples KRAS from upstream regulation and renders cancer cells resistant to SHP2 inhibitors

Teklab Gebregiworgis, Yoshihito Kano, Jonathan St-Germain, Nikolina Radulovich, Molly L. Udaskin, Ahmet Mentes, Richard Huang, Betty P. K. Poon, Wenguang He, Ivette Valencia-Sama, Claire M. Robinson, Melissa Huestis, Jinmin Miao, Jen Jen Yeh, Zhong-Yin Zhang, Meredith S. Irwin, Jeffrey E. Lee, Ming-Sound Tsao, Brian Raught, Christopher B. Marshall (), Michael Ohh () and Mitsuhiko Ikura ()
Additional contact information
Teklab Gebregiworgis: University Health Network
Yoshihito Kano: University of Toronto
Jonathan St-Germain: University Health Network
Nikolina Radulovich: University Health Network
Molly L. Udaskin: University Health Network
Ahmet Mentes: Black Diamond Therapeutics
Richard Huang: University of Toronto
Betty P. K. Poon: University of Toronto
Wenguang He: University of Toronto
Ivette Valencia-Sama: University of Toronto
Claire M. Robinson: University of Toronto
Melissa Huestis: University of Toronto
Jinmin Miao: Purdue University
Jen Jen Yeh: University of North Carolina
Zhong-Yin Zhang: Purdue University
Meredith S. Irwin: University of Toronto
Jeffrey E. Lee: University of Toronto
Ming-Sound Tsao: University Health Network
Brian Raught: University Health Network
Christopher B. Marshall: University Health Network
Michael Ohh: University of Toronto
Mitsuhiko Ikura: University Health Network

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Cancer cells bearing distinct KRAS mutations exhibit variable sensitivity to SHP2 inhibitors (SHP2i). Here we show that cells harboring KRAS Q61H are uniquely resistant to SHP2i, and investigate the underlying mechanisms using biophysics, molecular dynamics, and cell-based approaches. Q61H mutation impairs intrinsic and GAP-mediated GTP hydrolysis, and impedes activation by SOS1, but does not alter tyrosyl phosphorylation. Wild-type and Q61H-mutant KRAS are both phosphorylated by Src on Tyr32 and Tyr64 and dephosphorylated by SHP2, however, SHP2i does not reduce ERK phosphorylation in KRAS Q61H cells. Phosphorylation of wild-type and Gly12-mutant KRAS, which are associated with sensitivity to SHP2i, confers resistance to regulation by GAP and GEF activities and impairs binding to RAF, whereas the near-complete GAP/GEF-resistance of KRAS Q61H remains unaltered, and high-affinity RAF interaction is retained. SHP2 can stimulate KRAS signaling by modulating GEF/GAP activities and dephosphorylating KRAS, processes that fail to regulate signaling of the Q61H mutant.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26526-y

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DOI: 10.1038/s41467-021-26526-y

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