SHP2 inhibitors maintain TGFβ signalling through SMURF2 inhibition
Xianning Lai, Sarah Kit Leng Lui, Hiu Yan Lam, Yuta Adachi, Wen Jing Sim, Natali Vasilevski, Nicola J. Armstrong, Stephanie Claire Bridgeman,
Nathan Michael Main, Tuan Zea Tan, Janina E. E. Tirnitz-Parker, Jean Paul Thiery, Hiromichi Ebi, Alan Prem Kumar, and Pieter Johan Adam Eichhorn
Abstract
Despite the promising antitumor activity of SHP2 inhibitors in RAS-dependent tumours, overall responses have been limited by
their narrow therapeutic window. Like with all MAPK pathway inhibitors, this is likely the result of compensatory pathway activation
mechanisms. However, the underlying mechanisms of resistance to SHP2 inhibition remain unknown. The E3 ligase SMURF2 limits
TGFβ activity by ubiquitinating and targeting the TGFβ receptor for proteosome degradation. Using a functional RNAi screen
targeting all known phosphatases, we identify that the tyrosine phosphatase SHP2 is a critical regulator of TGFβ activity. Specifically,
SHP2 dephosphorylates two key residues on SMURF2, resulting in activation of the enzyme. Conversely, SHP2 depletion maintains
SMURF2 in an inactive state, resulting in the maintenance of TGFβ activity. Furthermore, we demonstrate that depleting SHP2 has
significant implications on TGFβ-mediated migration, senescence, and cell survival. These effects can be overcome through the use
of TGFβ-targeted therapies. Consequently, our findings provide a rationale for combining SHP2 and TGFβ inhibitors to enhance
tumour responses leading to improved patient outcomes.
npj Precision Oncology (2023)7:136 ; https://doi.org/10.1038/s41698-023-00486-6