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The Development of AXL Inhibitors in Lung Cancer: Recent Progress and Challenges
Yun Beom Sang1, Joo-Hang Kim1, Chang-Gon Kim2
1Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, South Korea.
Abstract:
AXL, along with MER and TYRO3, is a receptor tyrosine kinase from the TAM family. Although AXL itself is not thought to be a potent oncogenic driver, overexpression of AXL is known to trigger tumor cell growth, survival, invasion, metastasis, angiogenesis, epithelial to mesenchymal transition, and immune suppression. Overexpression of AXL is associated with therapy resistance and poor prognosis. Therefore, it is being studied as a marker of prognosis in cancer treatment or as a target in various cancer types. Recently, many preclinical and clinical studies on agents with various mechanisms targeting AXL have been actively conducted. They include small molecule inhibitors, monoclonal antibodies, and antibody-drug conjugates. This article reviewed the fundamental role of AXL in solid tumors, and the development in research of AXL inhibitors in recent years. Emphasis was placed on the function of AXL in acquired therapy resistance in patients with non-small cell lung cancer (NSCLC). Since clinical needs increase in NSCLC patients with acquired resistance after initial therapy, recent research efforts have focused on a combination treatment with AXL inhibitors and tyrosine kinase inhibitors or immunotherapy to overcome resistance. Lastly, we deal with challenges and limitations encountered in the development of AXL inhibitors.
Insights
AXL receptor tyrosine kinase overexpression drives cancer progression and therapy resistance, particularly in non-small cell lung cancer (NSCLC). Targeting AXL with inhibitors, especially in combination therapies, shows promise for overcoming resistance and improving patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- AXL receptor tyrosine kinase (RTK) overexpression promotes tumor growth, metastasis, and immune evasion.
- AXL is implicated in acquired resistance to cancer therapies and is associated with poor prognosis.
- AXL inhibitors are under investigation as therapeutic targets in various solid tumors.
Purpose of the Study:
- To review the role of AXL in solid tumors and recent advancements in AXL inhibitor research.
- To emphasize AXL's function in acquired therapy resistance in non-small cell lung cancer (NSCLC).
- To discuss combination treatment strategies involving AXL inhibitors for overcoming resistance.
Main Methods:
- Review of preclinical and clinical studies on AXL inhibitors.
- Analysis of AXL's role in acquired resistance mechanisms.
- Examination of combination therapies targeting AXL in NSCLC.
Main Results:
- AXL overexpression contributes to multiple hallmarks of cancer and therapy resistance.
- AXL inhibitors, including small molecules, antibodies, and antibody-drug conjugates, are in active development.
- Combination strategies with AXL inhibitors and TKIs or immunotherapy are being explored to overcome resistance in NSCLC.
Conclusions:
- AXL is a significant target for cancer therapy, particularly in overcoming acquired resistance.
- Targeting AXL, especially in combination regimens, holds potential for improving outcomes in NSCLC patients.
- Further research is needed to address challenges and limitations in AXL inhibitor development.
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