Abstract
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.
Highlights
Non-small cell lung carcinomas (NSCLC) commonly harbor oncogenic mutations in the Epidermal growth factor (EGF) receptor (EGFR), resulting in constitutive activation [1]
We evaluated the efficacy of Marsdenia tenacissima extract (MTE) in overcoming Axl- and Met- mediated erlotinib and gefitinib resistance in nonsmall cell lung cancer (NSCLC) in vitro and in vivo
Our data demonstrate that MTE is effective in epidermal growth factor receptor (EGFR)-Tyrosine kinase inhibitors (TKIs) resistant HCC827/ER NSCLC cells through co-inhibition of the EGFR downstream pathways and the bypass signaling molecules dictated by Met or Axl
Summary
Non-small cell lung carcinomas (NSCLC) commonly harbor oncogenic mutations in the EGF receptor (EGFR), resulting in constitutive activation [1]. When the corresponding receptor tyrosine kinases (RTKs) www.impactjournals.com/oncotarget are targeted by TKIs, this results in inhibition of key downstream signaling pathways such as the PI3K/Akt and MEK/ERK pathways, leading to cell growth arrest and death [4] While these drugs are highly effective, the majority of patients treated with them eventually acquire TKI resistance [5,6,7]. Recent studies have indicated that elevated expression of the eukaryotic translation initiation factor 4E (eIF4E) and the epithelial-to-mesenchymal transition (EMT) are linked to EGFR-TKIs resistance [13, 14] While these events are behind many cases of EGFR-TKI resistance, the mechanisms underlying acquired resistance to EGFRTKIs treatment are still unknown in over 40% of EGFRmutant NSCLC patients
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