SHP2 inhibitors maintain TGFβ signalling through SMURF2 inhibition.

Autor: Lai X; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.; NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore, Singapore.; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore., Lui SKL; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore., Lam HY; NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore, Singapore.; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore., Adachi Y; Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Aichi, 464-8681, Japan.; Division of Advanced Cancer Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8650, Japan., Sim WJ; Institute of Molecular and Cell Biology, A*STAR, Singapore, 138672, Singapore., Vasilevski N; Curtin Medical School, Faculty of Health Sciences, Curtin University, Bentley, WA, 6102, Australia.; Curtin Health Innovation Research Institute and Faculty of Health Sciences, Curtin University, Bentley, WA, 6102, Australia., Armstrong NJ; School of Electrical Engineering, Computing and Mathematical Sciences, Faculty of Science and Engineering, Curtin University, Bentley, WA, 6102, Australia., Bridgeman SC; Curtin Medical School, Faculty of Health Sciences, Curtin University, Bentley, WA, 6102, Australia.; Curtin Health Innovation Research Institute and Faculty of Health Sciences, Curtin University, Bentley, WA, 6102, Australia., Main NM; Curtin Medical School, Faculty of Health Sciences, Curtin University, Bentley, WA, 6102, Australia.; Curtin Health Innovation Research Institute and Faculty of Health Sciences, Curtin University, Bentley, WA, 6102, Australia., Tan TZ; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore., Tirnitz-Parker JEE; Curtin Medical School, Faculty of Health Sciences, Curtin University, Bentley, WA, 6102, Australia.; Curtin Health Innovation Research Institute and Faculty of Health Sciences, Curtin University, Bentley, WA, 6102, Australia., Thiery JP; Institute of Molecular and Cell Biology, A*STAR, Singapore, 138672, Singapore. tjp@visitor.nus.edu.sg.; Guangzhou Laboratory, Guangzhou International Bio Island, Haizhu District, Guangzhou, Guangdong, 510530, China. tjp@visitor.nus.edu.sg., Ebi H; Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, Nagoya, Aichi, 464-8681, Japan. hebi@aichi-cc.jp.; Division of Advanced Cancer Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 466-8650, Japan. hebi@aichi-cc.jp., Kumar AP; NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore, Singapore. apkumar@nus.edu.sg.; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore. apkumar@nus.edu.sg., Eichhorn PJA; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. Pieter.eichhorn@curtin.edu.au.; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore. Pieter.eichhorn@curtin.edu.au.; Curtin Medical School, Faculty of Health Sciences, Curtin University, Bentley, WA, 6102, Australia. Pieter.eichhorn@curtin.edu.au.; Curtin Health Innovation Research Institute and Faculty of Health Sciences, Curtin University, Bentley, WA, 6102, Australia. Pieter.eichhorn@curtin.edu.au.
Jazyk: angličtina
Zdroj: NPJ precision oncology [NPJ Precis Oncol] 2023 Dec 15; Vol. 7 (1), pp. 136. Date of Electronic Publication: 2023 Dec 15.
DOI: 10.1038/s41698-023-00486-6
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
Externí odkaz: