Anexelekto (AXL) Increases Resistance to EGFR-TKI and Activation of AKT and ERK1/2 in Non-Small Cell Lung Cancer Cells

Abstract

Recently, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized non-small cell lung cancer (NSCLC) treatment. However, resistance remains a major obstacle. Anexelekto (AXL) is a member of receptor tyrosine kinases (RTKs) and shares the same downstream signaling pathways with EGFR, such as PI3K/AKT and MAPK/ERK. AXL overexpression in resistant tumors has been implicated in many previous studies in vitro and in vivo. In this study, we further examined whether expression of AXL and its downstream targets increased in gefitinib-resistant PC9 cells (PC9GR). In addition, we hypothesize that knocking down AXL in PC9GR and overexpressing AXL in PC9 using genetic tools can restore and decrease the sensitivity to gefitinib, respectively. We found that silencing AXL could sensitize the resistance to gefitinib, and the downstream pathways were significantly inhibited. Interestingly, we also discovered that increased AXL expression did promote the resistance, and its downstream targets were activated accordingly. Then 69 NSCLC patients who harbored EGFR mutation were recruited to analyze the expression of AXL and the association between AXL expression and clinical characteristics. We found that 5 of the 69 patients were AXL positive (about 7%), and AXL was related to tumor differentiation and tumor size. In this study, we concluded that the molecular mechanisms of AXL mediated resistance involved in the increased activity of the PI3K/AKT and MAPK/ERK1/2 pathways, and AXL overexpression could promote resistance, but it can be weakened when AXL expression is silenced.

Acquired resistance to EGFR tyrosine kinase inhibitors is mediated by the reactivation of STC2/JUN/AXL signaling in lung cancer

“…AXL and EGFR share downstream signaling pathways including the PI3K/Akt and MAPK/ERK . AXL is frequently overexpressed in resistant tumors, where it contributes to EGFR TKI resistance . AXL is a compensatory survival signaling pathway, whereas EGFR is inactivated by EGFR TKIs.…”

Regulation of efferocytosis as a novel cancer therapy

“…Moreover, Axl could mediate resistance to chemotherapy [67], radiotherapy, and targeted molecular therapy in many cancers [68]. For instance, overexpression of Axl promotes resistance to EGFR-tyrosine kinase inhibitor (TKI) through the PI3K/Akt and MAPK/ERK signaling pathways [69]. In small-cell lung cancer, Axl promotes primary and acquired resistance to WEE1 (WEE1 G2 checkpoint kinase) inhibition.…”

Enapotamab vedotin, an AXL-specific antibody-drug conjugate, shows preclinical antitumor activity in non-small cell lung cancer

“…Enapotamab vedotin shows antitumor activity in EGFRi-resistant NSCLC PDX models in vivo. Because AXL upregulation has been described to be a common acquired resistance mechanism upon EGFRi treatment in both preclinical and clinical studies (8,9,22,23), we examined the effect of enapotamab vedotin in EGFRi-resistant models. The PDX model LXFA677, which is another EGFR-wild-type NSCLC model, albeit driven by EGFR activation, was rendered resistant against EGFRi by continuous in vivo exposure to gefitinib (24).…”