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

Journal volume & issue
Vol. 12, no. 1
pp. 1 – 15


Read online

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.