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    • In conclusion AXL overexpression preexisted in a subgroup of

    2024-04-18

    In conclusion, AXL overexpression preexisted in a subgroup of treatment-naive lung adenocarcinoma specimens harboring an activating EGFR mutation or in those with wild-type EGFR. Anti-AXL therapeutics delivered up front in combination with the EGFR inhibitor might overcome intrinsic or acquired resistance in patients with AXL-positive, EGFR wild-type, or EGFR-mutant NSCLC patients. Further work should focus on how AXL+ and AXL− groups are different in their response to chemotherapy to clarify its predictive value for anti-EGFR therapy in lung adenocarcinoma patients.
    Ethical declaration
    Introduction Epidermal growth factor receptor (EGFR) gene mutations were identified following the sequencing of 47 out of 58 receptor tyrosine kinase (RTKs) in tumors of non-small cell lung cancer (NSCLC) patients (Paez et al., 2004). EGFR mutations, mostly small in-frame exon 19 deletions and amino Cinacalcet australia substitutions within exon 21, like Leu858Arg, are sensitive to EGFR tyrosine kinase inhibitors (TKIs) gefitinib (Paez et al., 2004; Lynch et al., 2004) and erlotinib (Rosell et al., 2009). Despite the higher response rate and longer progression-free survival, there is no survival benefit with erlotinib in patients with EGFR mutations (Tsao et al., 2005). EGFR-mutation-positive lung cancer cells undergo apoptosis following EGFR knockdown, or pharmacological inhibition of AKT and signal transducer and activator of transcription 3 (STAT3), while they are relatively resistant when treated with chemotherapy (Sordella et al., 2004). Despite these observations, studies have focused on comparing EGFR TKIs versus chemotherapy for EGFR-mutation-positive NSCLC. Phase 3 trials have compared gefitinib or erlotinib with chemotherapy, confirming the significantly longer progression-free survival with EGFR TKIs (Mok et al., 2009; Rosell et al., 2012). The second-generation irreversible EGFR TKIs, afatinib and dacomitinib, have been found to be superior to gefitinib (Park et al., 2016; Wu et al., 2017). Osimertinib, a third-generation irreversible EGFR-TKI that inhibits also the EGFR Thr790Met point resistant mutation, yields significantly longer progression-free survival in comparison with standard EGFR TKIs as first-line treatment (Soria et al., 2018). Complete responses are uncommon, regardless of the EGFR TKI, and patients ultimately succumb to the disease. EGFR-mutation-positive NSCLC expresses multiple RTKs and/or non-RTKs, mainly focal adhesion kinase (FAK), encoded by the protein tyrosine kinase 2 (PTK2) gene and Src family kinases (SFK) (Rikova et al., 2007). EGFR inhibition increases the phosphorylation of the co-existing non-targeted RTKs, maintaining redundant downstream signaling (Stommel et al., 2007). Inter-receptor crosstalk of MET, integrin beta-4, erythropoietin-producing hepatocellular (EphA2), CUB domain-containing protein-1 (CDCP1) and AXL was described in EGFR-mutation-positive NSCLC (Gusenbauer et al., 2013). Numerous co-expressed RTKs and non-RTKs were observed in the EGFR-mutation-positive PC9 and PC9 gefitinib-resistant cells. The combination of afatinib or osimertinib with the Src inhibitor dasatinib caused tumor regression in EGFR-mutation-positive cells (Yoshida et al., 2014; Ichihara et al., 2017). SFK and FAK induce resistance to afatinib, erlotinib and osimertinib (Murakami et al., 2017). Moreover, RTK-driven cancers depend on Src-homology 2 domain-containing phosphatase 2 (SHP2), encoded by the protein tyrosine phosphatase, non-receptor type 11 (PTPN11) gene and SFKs for survival (Sausgruber et al., 2015). We reported that either gefitinib or osimertinib activates STAT3 and Src-YES-associated protein 1 (YAP1) in EGFR-mutation-positive lung cancer cells (Chaib et al., 2017). STAT3, when activated, translocates into the nucleus and promotes gene transcription (Gao et al., 2007). Combined EGFR, STAT3 and Src inhibition abrogated tumor growth more efficiently than single EGFR inhibition both in culture and in vivo (Chaib et al., 2017). AXL was identified as a downstream target of YAP1 in hepatocellular carcinoma (Xu et al., 2011). We noted that in EGFR TKI resistant cells, due to either EGFR Thr790Met point resistant mutation or AXL overexpression (Zhang et al., 2012), afatinib combined with a STAT3 blocker induced tumor growth regression (Codony-Servat et al., 2017).