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Analysis of Tumor Heterogeneity Through AXL Activation in Primary Resistance to EGFR Tyrosine Kinase Inhibitors
Ryota Nakamura1, Hiroyuki Fujii1, Tadaaki Yamada1
1Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Introduction:
EGFR tyrosine kinase inhibitors are standard therapeutic agents for patients with advanced NSCLC harboring EGFR mutations. Nevertheless, some patients exhibit primary resistance to EGFR tyrosine kinase inhibitors in the first-line treatment setting. AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is involved in primary resistance to EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC.
Methods:
We investigated spatial tumor heterogeneity using autopsy specimens and a patient-derived cell line from a patient with EGFR-mutated NSCLC having primary resistance to erlotinib plus ramucirumab.
Results:
Quantitative polymerase chain reaction analysis revealed that AXL mRNA expression differed at each metastatic site. In addition, AXL expression levels were likely to be negatively correlated with the effectiveness of erlotinib plus ramucirumab therapy. Analysis of a patient-derived cell line established from the left pleural effusion before initiation of treatment revealed that the combination of EGFR tyrosine kinase inhibitors and an AXL inhibitor remarkably inhibited cell viability and increased cell apoptosis in comparison with EGFR tyrosine kinase inhibitor monotherapy or combination therapy of these inhibitors with ramucirumab.
Conclusions:
Our observations suggest that AXL expression may play a critical role in the progression of spatial tumor heterogeneity and primary resistance to EGFR tyrosine kinase inhibitors in patients with EGFR-mutated NSCLC.
Insights
AXL receptor tyrosine kinase expression contributes to primary resistance against EGFR tyrosine kinase inhibitors in non-small cell lung cancer. Targeting AXL alongside EGFR inhibitors may overcome this resistance.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard treatments for advanced non-small cell lung cancer (NSCLC) with EGFR mutations.
- Primary resistance to first-line EGFR TKIs occurs in some patients, necessitating investigation into resistance mechanisms.
Purpose of the Study:
- To investigate the role of AXL receptor tyrosine kinase in spatial tumor heterogeneity and primary resistance to EGFR TKIs in EGFR-mutated NSCLC.
- To evaluate the therapeutic potential of combining EGFR TKIs with AXL inhibitors.
Main Methods:
- Analysis of autopsy specimens and a patient-derived cell line from an EGFR-mutated NSCLC patient with primary resistance to erlotinib plus ramucirumab.
- Quantitative polymerase chain reaction (qPCR) to assess AXL mRNA expression across metastatic sites.
- In vitro cell viability and apoptosis assays using EGFR TKIs, AXL inhibitors, and ramucirumab.
Main Results:
- AXL mRNA expression varied significantly across different metastatic sites.
- Higher AXL expression levels correlated with reduced effectiveness of erlotinib plus ramucirumab therapy.
- Combination therapy with EGFR TKIs and an AXL inhibitor significantly reduced cell viability and increased apoptosis compared to monotherapy or combination with ramucirumab.
Conclusions:
- AXL receptor tyrosine kinase expression is implicated in spatial tumor heterogeneity and primary resistance to EGFR TKIs in EGFR-mutated NSCLC.
- Targeting AXL in combination with EGFR TKIs shows promise for overcoming primary resistance and improving treatment outcomes.
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