ArticleMolecular oncology2023
Rational combination of SHP2 and mTOR inhibition for the treatment of hepatocellular carcinoma.
Article in Molecular oncology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 13 citations in OpenAlex.
- Targeted therapeutic strategies forTranslational lung cancer research · 2026Review
- SHP2 as a pivotal modulator of the tumor microenvironment in gastrointestinal cancers: from mechanisms to targeted therapies.Journal of translational medicine · 2026Review
- Discovering anticancer drug target combinations via network-informed signaling-based approach.Communications medicine · 2025Article
- RAS Pathway Inhibitors Combined with Targeted Agents Are Active in Patient-Derived Spheroids with Oncogenic KRAS Variants from Multiple Cancer Types.Cancer research communications · 2025Article
- Novel receptor tyrosine kinase-targeted strategies to overcome resistance in oral squamous cell carcinoma.Pharmacological reports : PR · 2025Review
- Article
- Molecular principles underlying aggressive cancers.Signal transduction and targeted therapy · 2025Review
- Anticancer Target Combinations: Network-Informed Signaling-Based Approach to Discovery.bioRxiv : the preprint server for biology · 2024Article
- Therapeutic potential of targeting protein tyrosine phosphatases in liver diseases.Acta pharmaceutica Sinica. B · 2024Review
- Tyrosine phosphataseFrontiers in immunology · 2024Review
- Targeting Protein Phosphatases for the Treatment of Chronic Liver Disease.Current drug targets · 2024Review
- SHP2: A Pleiotropic Target at the Interface of Cancer and Its Microenvironment.Cancer discovery · 2023Review
- Comprehensive Analysis of NKX3.2 in Liver Hepatocellular Carcinoma by Bigdata.Medicina (Kaunas, Lithuania) · 2023Article
Corrections and comments
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Authors and funding
16 authors at 2 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.