Rational combination of SHP2 and mTOR inhibition for the treatment of hepatocellular carcinoma.
SHP2
combination
hepatocellular carcinoma
mTOR
receptor tyrosine kinases
therapy
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
Jun 2023
Jun 2023
Historique:
revised:
07
11
2022
received:
17
09
2022
accepted:
12
01
2023
medline:
12
6
2023
pubmed:
19
1
2023
entrez:
18
1
2023
Statut:
ppublish
Résumé
Liver cancer is the fourth most common cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) being the main primary malignancy affecting the liver. Unfortunately, there are still limited therapeutic options for HCC, and even the latest advances have only increased the overall survival modestly. Thus, new treatment strategies and rational drug combinations are urgently needed. Reactivation of receptor tyrosine kinases (RTK) has been described as a mechanism of intrinsic resistance to targeted therapies in a variety of cancers, including inhibitors of mTOR. The design of rational combination therapies to overcome this type of resistance is complicated by the notion that multiple RTK can be upregulated during the acquisition of resistance. SHP2, encoded by the gene PTPN11, acts downstream of virtually all RTK, and has proven to be a good target for small molecule inhibitors. Here, we report activation of multiple RTK upon mTOR inhibition in HCC which, through SHP2, leads to reactivation of the mTOR pathway. We show that co-inhibition of both mTOR and SHP2 is highly synergistic in vitro by triggering apoptosis. More importantly, the combination is well-tolerated and outperforms the monotherapies in impairing tumor growth in multiple HCC mouse models. Our findings suggest a novel rational combination therapy for the treatment of HCC.
Identifiants
pubmed: 36650715
doi: 10.1002/1878-0261.13377
pmc: PMC10257427
doi:
Substances chimiques
TOR Serine-Threonine Kinases
EC 2.7.11.1
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
964-980Subventions
Organisme : National Natural Science Foundation of China
ID : 82072633
Organisme : This work was funded by the American Association for Cancer Research, Lustgarten Foundation, and Stand Up to Cancer as a Pancreatic Cancer Collective New Therapies Challenge grant
ID : SU2C-AACR-PCC-01-18
Informations de copyright
© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
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