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  • AXL is a member of the TAM Tyro Axl

    2024-05-23

    AXL is a member of the TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases (RTKs) [4]. Elevated AXL expression could promote oncogenic processes such as cell growth, migration, invasion, and epithelial-to-mesenchymal transition (EMT), which substantially contribute to tumor progression and poor prognosis [5], [6], [7], [8], [9], [10]. Recently, AXL has been a focus of research in modulating resistance to conventional and targeted cancer therapies for several types of cancers [11], [12], [13]. In NSCLC cells, it was reported that AXL expression was involved in the process of acquired resistance to the EGFR-TKI erlotinib [14] and the EGFR monoclonal antibody cetuximab [15]. In addition, AXL was overexpressed in several wild-type EGFR NSCLC cell lines (eg, A549 and H460) that were intrinsically resistant to EGFR-TKI [16]. Genetic or pharmacologic inhibition of AXL could sensitize NSCLC 366 2 australia to erlotinib or significantly inhibit cell growth [14], [15], [16]. Collectively, AXL might mediate both acquired and intrinsic resistance to EGFR inhibitors in NSCLC. Although the underlying mechanisms involved in RTK inhibitor resistance are not well understood, activation of alternative RTKs or cross talk between these signals has been identified as an important resistance process because of signaling diversification [17]. In triple-negative breast cancers that are intrinsically resistant to anti-EGFR agents, EGF-mediated activation of EGFR can also induce the coactivation of AXL, demonstrating that AXL diversified EGFR signaling and limited the response to EGFR-targeted inhibitors [18]. Moreover, in an EGFR wild-type NSCLC cell model of acquired resistance to cetuximab, AXL activation stimulated EGFR activation, and EGFR directly regulated the expression of AXL mRNA through MAPK signaling, suggesting that there is a positive-feedback loop between AXL and EGFR signaling [15]. Furthermore, it has been shown that several RTKs, such as EGFR, AXL, MAP2K, and IGF1R, are activated and expressed at above average concentrations in NSCLC cell lines [19]. To date, the relationship between AXL and EGFR in human primary NSCLC and the association of AXL expression with EGFR mutation status in treatment-naive lung adenocarcinomas remain to be determined. In this study, we aimed to investigate the coexpression pattern of AXL and EGFR signaling in EGFR wild-type and EGFR-mutant lung adenocarcinoma patients by determining the common EGFR-activating mutation status (exon 19 deletions and exon 21 L858R) in 109 lung adenocarcinoma patients using polymerase chain reaction (PCR) direct sequencing and amplification-refractory mutation-specific (ARMS) assays; evaluating the clinicopathologic significance of AXL, EGFR, and pEGFR1068 expression in the 109 initial tumor specimens using immunohistochemical studies; and investigating the possible relationships between AXL and EGFR signals in EGFR-mutant and wild-type patient cohorts.
    Methods
    Results
    Discussion With increasing evidence supporting the role of AXL in the resistance to anti-EGFR agents, the development of anti-AXL therapeutics is essential. However, whether AXL inhibition should be delivered up front in combination with the EGFR inhibitor in an attempt to prevent or delay resistance or whether it should be administered as a second-line therapy to overcome established resistance remains to be determined. Our study demonstrated that AXL overexpression is already present in the initial tumor population in approximately half of the lung adenocarcinoma patients harboring an activating mutation of EGFR and in more than 60% of patients with wild-type EGFR. Furthermore, AXL and EGFR were coexpressed in a subgroup of treatment-naive lung adenocarcinomas with or without EGFR mutations. Incorporating AXL expression as a predictive biomarker of drug resistance might help to determine the timing of anti-AXL therapeutic delivery to overcome resistance to EGFR-targeted therapy in NSCLCs.