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The Role of Axl Inhibition and Immune Checkpoint Blockade in Non-small Cell Lung Cancer: Current Understanding and
Tae Woo Kim1, Sung Hwan Kim1, Hyun Ju DO1
1New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI Hub), Daegu, Republic of Korea.
Abstract:
Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases and demonstrates limited responsiveness to traditional chemotherapy and radiation. Recent advancements in targeted therapies and immune checkpoint inhibitors (ICIs) have transformed NSCLC treatment, yet resistance mechanisms remain a challenge. Axl, a receptor tyrosine kinase over-expressed in NSCLC, drives tumor progression, epithelial-mesenchymal transition (EMT), and resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and ICIs. Preclinical studies highlight the efficacy of Axl inhibitors, such as bemcentinib, brigatinib, and enapotamab vedotin, in overcoming drug resistance and enhancing immune responses. Clinical trials combining Axl inhibitors with ICIs (e.g., pembrolizumab) show promise, particularly in STK11-mutant NSCLC, with manageable toxicity profiles. However, challenges persist in optimizing dosing, managing adverse events, and identifying predictive biomarkers. Ongoing research into combination strategies and biomarker-driven approaches aims to refine Axl-targeted therapies and improve outcomes for patients with advanced NSCLC.
Insights
Targeting Axl receptor tyrosine kinase shows promise for overcoming resistance in non-small cell lung cancer (NSCLC) treatments. Combination therapies with Axl inhibitors and immune checkpoint inhibitors (ICIs) offer new hope for advanced NSCLC patients.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- Non-small cell lung cancer (NSCLC) is the most common lung cancer subtype, often resistant to conventional therapies.
- Axl receptor tyrosine kinase overexpression in NSCLC promotes tumor growth, epithelial-mesenchymal transition (EMT), and resistance to targeted therapies and immunotherapies.
- Resistance to current treatments remains a significant challenge in managing advanced NSCLC.
Purpose of the Study:
- To review the role of Axl receptor tyrosine kinase in NSCLC progression and treatment resistance.
- To evaluate the therapeutic potential of Axl inhibitors, alone and in combination with immune checkpoint inhibitors (ICIs), for NSCLC.
- To discuss current challenges and future directions in Axl-targeted therapy for NSCLC.
Main Methods:
- Review of preclinical studies on Axl inhibitors (bemcentinib, brigatinib, enapotamab vedotin) in NSCLC models.
- Analysis of clinical trial data investigating combinations of Axl inhibitors with ICIs (e.g., pembrolizumab).
- Examination of Axl's role in mediating resistance to EGFR tyrosine kinase inhibitors (TKIs) and ICIs.
Main Results:
- Axl inhibition demonstrates efficacy in preclinical models by overcoming drug resistance and enhancing anti-tumor immune responses.
- Clinical trials combining Axl inhibitors with ICIs show promising results, especially in STK11-mutant NSCLC, with acceptable toxicity.
- Axl signaling is implicated in resistance to both EGFR TKIs and ICIs in NSCLC.
Conclusions:
- Axl inhibitors represent a promising therapeutic strategy for overcoming treatment resistance in NSCLC.
- Combination therapy with Axl inhibitors and ICIs holds potential for improving outcomes in advanced NSCLC, particularly in specific patient subgroups.
- Further research is needed to optimize dosing, identify predictive biomarkers, and manage adverse events for Axl-targeted therapies.
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