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Targeting the HGF/MET Axis in Cancer Therapy: Challenges in Resistance and Opportunities for Improvement
Xing Huang1,2,3, Enliang Li1,2,3, Hang Shen1,2,3
1Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Abstract:
Among hundreds of thousands of signal receptors contributing to oncogenic activation, tumorigenesis, and metastasis, the hepatocyte growth factor (HGF) receptor - also called tyrosine kinase MET - is a promising target in cancer therapy as its axis is involved in several different cancer types. It is also associated with poor outcomes and is involved in the development of therapeutic resistance. Several HGF/MET-neutralizing antibodies and MET kinase-specific small molecule inhibitors have been developed, resulting in some context-dependent progress in multiple cancer treatments. Nevertheless, the concomitant therapeutic resistance largely inhibits the translation of such targeted drug candidates into clinical application. Until now, numerous studies have been performed to understand the molecular, cellular, and upstream mechanisms that regulate HGF/MET-targeted drug resistance, further explore novel strategies to reduce the occurrence of resistance, and improve therapeutic efficacy after resistance. Intriguingly, emerging evidence has revealed that, in addition to its conventional function as an oncogene, the HGF/MET axis stands at the crossroads of tumor autophagy, immunity, and microenvironment. Based on current progress, this review summarizes the current challenges and simultaneously proposes future opportunities for HGF/MET targeting for therapeutic cancer interventions.
Insights
Targeting the hepatocyte growth factor (HGF)/MET pathway shows promise in cancer therapy but faces resistance. This review explores challenges and opportunities for HGF/MET targeting to improve cancer treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The hepatocyte growth factor (HGF)/MET signaling axis is implicated in oncogenesis, metastasis, and therapeutic resistance across various cancers.
- HGF/MET pathway activation is linked to poor patient outcomes and hinders the effectiveness of targeted therapies.
- Existing HGF/MET-targeted therapies, including antibodies and small molecule inhibitors, have shown limited success due to widespread drug resistance.
Purpose of the Study:
- To review current understanding of molecular mechanisms driving HGF/MET-targeted drug resistance in cancer.
- To explore novel strategies for overcoming or preventing therapeutic resistance to HGF/MET inhibitors.
- To discuss the emerging roles of the HGF/MET axis in tumor autophagy, immunity, and the tumor microenvironment.
Main Methods:
- Literature review of studies investigating HGF/MET signaling in cancer.
- Analysis of mechanisms underlying therapeutic resistance to HGF/MET-targeted agents.
- Synthesis of current research on HGF/MET's interaction with tumor microenvironment components.
Main Results:
- Therapeutic resistance remains a significant obstacle to clinical translation of HGF/MET-targeted drugs.
- The HGF/MET axis plays a complex role beyond oncogenesis, influencing autophagy, immune responses, and the tumor microenvironment.
- Understanding these multifaceted roles is crucial for developing effective therapeutic strategies.
Conclusions:
- Despite challenges posed by drug resistance, the HGF/MET pathway remains a critical target in oncology.
- Future research should focus on combination therapies and targeting the HGF/MET axis within its broader biological context.
- Addressing resistance mechanisms and leveraging HGF/MET's role in the tumor microenvironment offers opportunities to enhance cancer treatment outcomes.
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