ArticleHepatology (Baltimore, Md.)2020
Overriding Adaptive Resistance to Sorafenib Through Combination Therapy With Src Homology 2 Domain-Containing Phosphatase 2 Blockade in Hepatocellular Carcinoma.
Article in Hepatology (Baltimore, Md.), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 84 citations in OpenAlex.
- Inhibition of SHP2 enhances the effects of selective receptor tyrosine kinase inhibitors in untreated preclinical models of RET-mutated thyroid cancer.Investigational new drugs · 2026Article
- SHP2 as a pivotal modulator of the tumor microenvironment in gastrointestinal cancers: from mechanisms to targeted therapies.Journal of translational medicine · 2026Review
- TP53, HIF1A, and CDKN2A in Hepatocellular Carcinoma: Roles in Senescence, Ferroptosis, and Prognosis.Clinical and translational gastroenterology · 2026Article
- Translating Pharmacology from Animal Models to Organoids: Advancing Predictive Human Biology in Drug Discovery.Stem cell reviews and reports · 2026Review
- Alcohol induces sorafenib resistance in hepatocellular carcinoma: A translational study.Journal of molecular medicine (Berlin, Germany) · 2026Article
- RETRACTED: NFIC suppressed the development of Glioma via modulating the balance of SHP2/PI3K and NF-κB/PTEN Signaling.PloS one · 2026Article
- The advantages and challenges of sorafenib combination therapy: Drug resistance, toxicity and future directions (Review).Oncology letters · 2025Review
- State-of-the-Art Liver Cancer Organoids: Modeling Cancer Stem Cell Heterogeneity for Personalized Treatment.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2025Review
- Hepatobiliary organoid research: the progress and applications.Frontiers in pharmacology · 2025Review
- Current status and new directions for hepatocellular carcinoma diagnosis.Liver research (Beijing, China) · 2024Review
- COLEC10 inhibits the stemness of hepatocellular carcinoma by suppressing the activity of β-catenin signaling.Cellular oncology (Dordrecht, Netherlands) · 2024Article
- Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies.MedComm · 2024Review
- CuET overcomes regorafenib resistance by inhibiting epithelial-mesenchymal transition through suppression of the ERK pathway in hepatocellular carcinoma.Translational oncology · 2024Article
- WWP1 inhibition increases SHP2 inhibitor efficacy in colorectal cancer.NPJ precision oncology · 2024Article
- Off-target autophagy inhibition by SHP2 allosteric inhibitors contributes to their antitumor activity in RAS-driven cancers.The Journal of clinical investigation · 2024Article
- Advances in hepatocellular carcinoma drug resistance models.Frontiers in medicine · 2024Review
- From MASH to HCC: the role of Gas6/TAM receptors.Frontiers in immunology · 2024Review
- Tyrosine phosphataseFrontiers in immunology · 2024Review
- Human patient derived organoids: an emerging precision medicine model for gastrointestinal cancer research.Frontiers in cell and developmental biology · 2024Review
- [Progress and application of liver organoids in the study of liver cancer].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2023Article
1 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND AND
aimsThe survival benefit of sorafenib for patients with hepatocellular carcinoma (HCC) is unsatisfactory due to the development of adaptive resistance. Increasing evidence has demonstrated that drug resistance can be acquired by cancer cells by activating a number of signaling pathways through receptor tyrosine kinases (RTKs); nevertheless, the detailed mechanism for the activation of these alternative pathways is not fully understood. APPROACH AND
resultsGiven the physiological role of Src homology 2 domain-containing phosphatase 2 (SHP2) as a downstream effector of many RTKs for activation of various signaling cascades, we first found that SHP2 was markedly up-regulated in our established sorafenib-resistant cell lines as well as patient-derived xenografts. Upon sorafenib treatment, adaptive resistance was acquired in HCC cells through activation of RTKs including AXL, epidermal growth factor receptor, EPH receptor A2, and insulin-like growth factor 1 receptor, leading to RAS/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK), and AKT reactivation. We found that the SHP2 inhibitor SHP099 abrogated sorafenib resistance in HCC cell lines and organoid culture in vitro by blocking this negative feedback mechanism. Interestingly, this sensitization effect was also mediated by induction of cellular senescence. SHP099 in combination with sorafenib was highly efficacious in the treatment of xenografts and genetically engineered models of HCC.
conclusionsSHP2 blockade by SHP099 in combination with sorafenib attenuated the adaptive resistance to sorafenib by impeding RTK-induced reactivation of the MEK/ERK and AKT signaling pathways. SHP099 in combination with sorafenib may be a safe therapeutic strategy against HCC.
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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.