Marsdenia tenacissima extract overcomes Axl- and Met-mediated erlotinib and gefitinib cross-resistance in non-small cell lung cancer cells

Tyrosine kinase inhibitors (TKIs) are an effective treatment strategy for non-small cell lung cancer (NSCLC) patients harboring mutations that result in constitutive activation of the epidermal growth factor receptor (EGFR). However, most patients eventually develop resistance to TKIs. This occurs due to additional EGFR mutations or the activation of bypass signaling pathways. In our previous work, we demonstrated that Marsdenia tenacissima extract (MTE) restored gefitinib sensitivity in resistant NSCLC cells with EGFR T790M or K-ras mutations. However, the potential efficacy of MTE in NSCLC cells with resistance mediated by Axl and c-Met, and the related molecular mechanisms need to be elucidated. In this study we evaluated the ability of MTE to restore erlotinib/gefitinib sensitivity in TKI resistant HCC827/ER cells and xenograft mice models. Our results demonstrate that MTE overcomes erlotinib and gefitinib resistance driven by Axl and c-Met in vitro and in vivo. Combination therapy significantly suppressed EGFR downstream molecules and the c-Met and Axl activated bypass signaling pathways. Moreover, we observed that MTE is more efficient at restoring resistance to erlotinib than gefitinib. As the Axl and c-Met mediated bypass pathways share the same downstream signaling cascade as EGFR, simultaneous targeting of these pathways is a promising strategy to overcome acquired resistance of TKIs. Our results demonstrate that MTE treatment attenuates Axl phosphorylation and the associated epithelial-mesenchymal transition, suggesting MTE treatment may be a potential therapeutic strategy for overcoming erlotinib and gefitinib cross-resistance in NSCLC, especially for erlotinib resistance.