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    • For the NSCLC patients with EGFR

    2022-11-09

    For the NSCLC patients with EGFR-activating mutations, EGFR-TKIs (gefitinib and erlotinib) are effective clinical therapies [21], [22]. However, approximately 10% of patients harboring EGFR-sensitizing mutations exhibit intrinsic resistance, and up to 40% do not attain a major response to treatment [23], [24]. The mechanisms of intrinsic resistance to EGFR-TKI in the presence of sensitizing mutations are relatively unknown. Resistance might be due to the presence of K-Ras mutations [25], T790M-resistant mutations or other Hydrochlorothiazide australia 20 insertions or duplications [26], [27], differences in expression levels of cellular apoptotic machinery components (eg, BIM) [28], [29], high CRIPTO1 expression [30], and MET amplification [31] in EGFR-mutant tumors before TKI exposure. Although MET amplification and T790M are the most common mechanisms of acquired resistance to EGFR-TKI, they might also be subclonal drivers that promote intrinsic resistance when present de novo at sufficient frequencies [32]. Similarly, AXL is critical for the development of acquired resistance to TKIs in NSCLC [14], [15]; however, it is uncertain to what extent AXL overexpression is already present in treatment-naive EGFR mutant lung adenocarcinoma patients. In this study, we demonstrated that AXL expression was scored positive in 51.5% of lung adenocarcinoma patients harboring EGFR-activating mutations. Furthermore, the percentage of AXL+/EGFR+, AXL+/pEGFR1068+, and AXL+/EGFR+/pEGFR1068+ coexpression was approximately 60%-70% among the AXL+ patients with EGFR-activating mutations, suggesting that AXL might act as a redundant pathway to maintain downstream signals in case the primary affected EGFR signaling pathway is blocked. Therefore, AXL overexpression might be associated with earlier acquired resistance when under the selection pressure of EGFR inhibitors, or it may contribute to the intrinsic resistance to EGFR-TKIs in lung adenocarcinoma patients harboring EGFR-activating mutations. Clinically, AXL inhibition might be delivered up front in combination with the EGFR inhibitor to prevent or delay resistance in these AXL-positive NSCLC patients with EGFR-activating mutations. For the NSCLC patients with wild-type EGFR, anti-EGFR monoclonal antibodies have been demonstrated to be effective clinical therapies in EGFR-positive advanced NSCLC patients [33]. In addition, a subgroup of patients with wild-type EGFR also seems to benefit from EGFR-TKI treatment, although there are currently no validated markers for identifying these patients [34], [35]. Recently, Byers et al [16] reported that AXL is a novel marker of EMT in NSCLC and is also a pivotal mediator of resistance to EGFR inhibitors in both EGFR-mutant and wild-type NSCLC with a mesenchymal phenotype. In cell lines expressing high levels of AXL and EGFR (such as A549, H1299, H460, and H2882), inhibition of AXL by the specific kinase inhibitor SGI-7079 was able to sensitize cells to erlotinib, first demonstrating that AXL inhibition enhanced responses to EGFR inhibitors in NSCLCs that were intrinsically resistant to TKIs in the setting of wild-type EGFR[21]. Moreover, Brand et al [15] most recently reported that AXL was overexpressed and hyperactivated in head and neck squamous cell carcinoma patient–derived xenografts that were intrinsically resistant to cetuximab therapy compared with the cetuximab-sensitive patient-derived xenografts, suggesting that AXL may mediate intrinsic resistance to cetuximab in head and neck squamous cell carcinoma patients. In breast cancer, it was demonstrated that AXL diversified EGFR signaling and limited the response to EGFR-targeted inhibitors in triple-negative breast cancer cells [19]. To date, the possible mechanisms for AXL’s involvement in intrinsic resistance to EGFR inhibitors are related to EMT, or transactivation or cross talk between AXL and EGFR [15], [16], [19]. Here, we demonstrated that AXL was overexpressed in approximately 60% of patients with wild-type EGFR, and half of the AXL+ patients exhibited AXL+/EGFR+ coexpression. Our results suggested that anti-AXL therapeutics might be essential in AXL+ patients, and cotargeting AXL and EGFR may be a means by which to overcome intrinsic resistance to anti-EGFR therapy in AXL+/EGFR+ wild-type NSCLC patients.