Abstract
BackgroundNon‐small cell lung cancer (NSCLC) positive for activating mutations of the epidermal growth factor receptor (EGFR) gene is initially sensitive to EGFR‐tyrosine kinase inhibitors (TKIs) but eventually develops resistance to these drugs. Upregulation of the receptor tyrosine kinase AXL in tumor tissue has been detected in about one‐fifth of NSCLC patients with acquired resistance to EGFR‐TKIs. However, the clinical relevance of the levels of AXL and its ligand GAS6 in plasma remains unknown.MethodsTumor tissue and plasma specimens were collected from 25 EGFR‐mutated NSCLC patients before EGFR‐TKI treatment or after treatment failure. The levels of AXL and of GAS6 mRNA in tumor tissue were evaluated by immunohistochemistry and chromogenic in situ hybridization, respectively. The plasma concentrations of AXL and GAS6 were measured with enzyme‐linked immunosorbent assays.ResultsAXL expression was detected in three of 12 (25%) and nine of 19 (47%) tumor specimens obtained before and after EGFR‐TKI treatment, respectively. All tumor specimens assayed were positive for GAS6 mRNA. The median values for the plasma AXL concentration before and after EGFR TKI treatment were 1 635 and 1 460 pg/mL, respectively, and those for the plasma GAS6 concentration were 4 615 and 6 390 pg./mL, respectively. There was no significant correlation between the plasma levels of AXL or GAS6 and the corresponding expression levels in tumor tissue.ConclusionPlasma concentrations of AXL and GAS6 do not reflect tumor expression levels, and their measurement is thus not a viable alternative to direct analysis of tumor tissue in EGFR‐mutated NSCLC.
Highlights
Individuals with non-small cell lung cancer (NSCLC) positive for activating mutations of the epidermal growth factor receptor (EGFR) gene are sensitive to first- and secondgeneration EGFR–tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib
Twenty-five patients with Non-small cell lung cancer (NSCLC) positive for EGFR activating mutations who had tissue and plasma specimens collected before treatment with EGFR-TKIs or after the development of resistance to these drugs were enrolled in the study (Table 1)
Mechanisms of resistance to EGFR-TKIs other than T790M include MET amplification, overexpression of hepatocyte growth factor, activation of insulin-like growth factor–1 receptor signaling, and upregulation of AXL, and several agents that target these mechanisms are under development (ClinicalTrials.gov identifiers NCT02499614, NCT02495233, NCT03599518, and NCT02424617)
Summary
Individuals with non-small cell lung cancer (NSCLC) positive for activating mutations of the epidermal growth factor receptor (EGFR) gene are sensitive to first- and secondgeneration EGFR–tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib Most such tumors develop resistance to EGFR-TKIs within 10 to 14 months of treatment initiation.[1,2,3,4,5,6] Several mechanisms of acquired resistance to EGFR-TKIs have been identified, including the development of a secondary T790M mutation in exon 20 of EGFR, MET amplification, overexpression of hepatocyte growth factor, and activation of insulin-like growth factor-1 receptor signaling.[7,8] The T790M mutation of EGFR is the most common mechanism of such acquired resistance, having been detected in up to 50% of patients after failure of EGFR-TKI therapy.[7,8,9] Osimertinib is a third-generation, irreversible EGFR-TKI that was approved by the U.S Food and Drug Administration in November 2015 for the treatment of individuals with metastatic NSCLC positive for the. Conclusion: Plasma concentrations of AXL and GAS6 do not reflect tumor expression levels, and their measurement is not a viable alternative to direct analysis of tumor tissue in EGFR-mutated NSCLC
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
