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

• Published in: Nature communications Vol. 12; no. 1; p. 6274
• Main Authors: Gebregiworgis, Teklab, Kano, Yoshihito, St-Germain, Jonathan, Radulovich, Nikolina, Udaskin, Molly L., Mentes, Ahmet, Huang, Richard, Poon, Betty P. K., He, Wenguang, Valencia-Sama, Ivette, Robinson, Claire M., Huestis, Melissa, Miao, Jinmin, Yeh, Jen Jen, Zhang, Zhong-Yin, Irwin, Meredith S., Lee, Jeffrey E., Tsao, Ming-Sound, Raught, Brian, Marshall, Christopher B., Ohh, Michael, Ikura, Mitsuhiko
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/95; 631/45; 631/67; 82/16; 82/58; 82/6; 82/80; 82/83; Biophysics; Cancer; Cell Line, Tumor; Enzyme Inhibitors - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; Guanosine Triphosphate - metabolism; Humanities and Social Sciences; Humans; Inhibitors; K-Ras protein; Kinases; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; MAP kinase; Molecular dynamics; multidisciplinary; Mutants; Mutation; Mutation, Missense; Pancreatic cancer; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; raf Kinases - genetics; raf Kinases - metabolism; Raf protein; Science; Science (multidisciplinary); Sensitivity; Signaling; src-Family Kinases - genetics; src-Family Kinases - metabolism; Upstream

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...