Nature Communications (Nov 2021)
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,
- Mitsuhiko Ikura
Affiliations
- Teklab Gebregiworgis
- Princess Margaret Cancer Centre, University Health Network
- Yoshihito Kano
- Department of Laboratory Medicine and Pathobiology, University of Toronto
- Jonathan St-Germain
- Princess Margaret Cancer Centre, University Health Network
- Nikolina Radulovich
- Princess Margaret Cancer Centre, University Health Network
- Molly L. Udaskin
- Princess Margaret Cancer Centre, University Health Network
- Ahmet Mentes
- Black Diamond Therapeutics
- Richard Huang
- Department of Laboratory Medicine and Pathobiology, University of Toronto
- Betty P. K. Poon
- Department of Laboratory Medicine and Pathobiology, University of Toronto
- Wenguang He
- Department of Biochemistry, University of Toronto
- Ivette Valencia-Sama
- Department of Laboratory Medicine and Pathobiology, University of Toronto
- Claire M. Robinson
- Department of Laboratory Medicine and Pathobiology, University of Toronto
- Melissa Huestis
- Department of Laboratory Medicine and Pathobiology, University of Toronto
- Jinmin Miao
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research and Institute for Drug Discovery, Purdue University
- Jen Jen Yeh
- Lineberger Comprehensive Cancer Center and Departments of Surgery and Pharmacology, University of North Carolina
- Zhong-Yin Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research and Institute for Drug Discovery, Purdue University
- Meredith S. Irwin
- Department of Laboratory Medicine and Pathobiology, University of Toronto
- Jeffrey E. Lee
- Department of Laboratory Medicine and Pathobiology, University of Toronto
- Ming-Sound Tsao
- Princess Margaret Cancer Centre, University Health Network
- Brian Raught
- Princess Margaret Cancer Centre, University Health Network
- Christopher B. Marshall
- Princess Margaret Cancer Centre, University Health Network
- Michael Ohh
- Department of Laboratory Medicine and Pathobiology, University of Toronto
- Mitsuhiko Ikura
- Princess Margaret Cancer Centre, University Health Network
- DOI
- https://doi.org/10.1038/s41467-021-26526-y
- Journal volume & issue
-
Vol. 12,
no. 1
pp. 1 – 15
Abstract
SHP2 promotes RAS-driven MAPK signalling, but it is unclear why cancer cells with distinct KRAS mutations exhibit differential sensitivity to SHP2 inhibition. Here the authors show that KRAS Q61H is decoupled from SHP2- mediated upstream regulation, thus Q61H pancreatic cancer cells maintain MAPK signalling and are refractory to SHP2 inhibitors.
