Abstract
Gefitinib, erlotinib or afatinib are the current treatment for non-small-cell lung cancer (NSCLC) harboring an activating mutation of the epidermal growth factor receptor (EGFR), but less than 5% of patients achieve a complete response and the median progression-free survival is no longer than 12 months. Early adaptive resistance can occur as soon as two hours after starting treatment by activating signal transducer and activation of transcription 3 (STAT3) signaling. We investigated the activation of STAT3 in a panel of gefitinib-sensitive EGFR mutant cell lines, and gefitinib-resistant PC9 cell lines developed in our laboratory. Afatinib has great activity in gefitinib-sensitive as well as in gefitinib-resistant EGFR mutant NSCLC cell lines. However, afatinib therapy causes phosphorylation of STAT3 tyrosine 705 (pSTAT3Tyr705) and elevation of STAT3 and RANTES mRNA levels. The combination of afatinib with TPCA-1 (a STAT3 inhibitor) ablated pSTAT3Tyr705 and down-regulated STAT3 and RANTES mRNA levels with significant growth inhibitory effect in both gefitinib-sensitive and gefitinib-resistant EGFR mutant NSCLC cell lines. Aldehyde dehydrogenase positive (ALDH+) cells were still observed with the combination at the time that Hairy and Enhancer of Split 1 (HES1) mRNA expression was elevated following therapy. Although the combination of afatinib with STAT3 inhibition cannot eliminate the potential problem of a remnant cancer stem cell population, it represents a substantial advantage and opportunity to further prolong progression free survival and probably could increase the response rate in comparison to the current standard of single therapy.
Highlights
The epidermal growth factor receptor (EGFR)directed tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib and afatinib are approved therapies for non-small-cell lung cancer (NSCLC) harboring activating mutations in the EGFR kinase [1,2,3]
EGFR TKIs induce a significant number of radiographic responses, almost no complete responses www.impactjournals.com/oncotarget are obtained and the median progressionfree survival (PFS) does not exceed more than one year
As soon as EGFR mutations were discovered in NSCLC, they were associated with dramatic response to gefitinib [31, 32]
Summary
The epidermal growth factor receptor (EGFR)directed tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib and afatinib are approved therapies for non-small-cell lung cancer (NSCLC) harboring activating mutations in the EGFR kinase [1,2,3]. Gefitinib and erlotinib are reversible inhibitors that target the ATP-site of the kinase. Afatinib, a second generation irreversible epidermal growth factor family of receptor tyrosine kinases (ErbB) blocker, targets the ATP-site of the receptor, and covalently binds to cysteine 797 (C797) of EGFR which allows prolonged inhibition of EGFR phosphorylation, even in the presence of a T790M secondary mutation [4]. In mouse models of EGFR (L858R/T790M/C797S) driven lung cancer, a new compound that targets selected drug-resistant EGFR but spares the wild-type receptor is effective in combination with cetuximab, an antibody that blocks EGFR dimerization and keeps the receptor in its inactive form [8]. Afatinib induced downregulation of thymidylate synthase in the gefitinib-resistant NSCLC cells [9]
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