TPCA-1 is a direct dual inhibitor of STAT3 and NFκB and regresses mutant EGFR associated human non-small cell lung cancers
Menée in vitro, cette étude suggère l'intérêt d'un composé appelé TPCA-1, un inhibiteur des kinases IKK et de STAT3, en combinaison avec le gefitinib pour le traitement des cancers du poumon non à petites cellules présentant des mutations du gène EGFR
Epidermal growth factor receptor (EGFR) is a clinical therapeutic target to treat a subset of NSCLC harboring EGFR mutants. However, some patients with similar kind of EGFR mutation show intrinsic resistance to TKIs. It indicates that other key molecules are involved in the survival of these cancer cells. We showed here that TPCA-1, a previously reported inhibitor of IKKs, blocked STAT3 recruitment to upstream kinases by docking into SH2 domain of STAT3 and attenuated STAT3 activity induced by cytokines and cytoplasmic tyrosine kinases. TPCA-1 is an effective inhibitor of STAT3 phosphorylation, DNA-binding and transactivation in vivo. It selectively repressed proliferation of NSCLC cells with constitutive STAT3 activation. In addition, using pharmacological and genetic approaches, we found that both NFκB and STAT3 could regulate the transcripts of IL6 and COX2 in NSCLC harboring EGFR mutations. Moreover, gefitinib treatment only did not efficiently suppress NFκB and STAT3 activity. In contrast, we found that treatment with TKIs increased phosho-STAT3 level in target cells. Inhibiting EGFR, STAT3 and NFκB by combination of TKIs with TPCA-1 showed increased sensitivity and enhanced apoptosis induced by gefitinib. Collectively, in this work, we identified TPCA-1 as a direct dual inhibitor for both IKKs and STAT3, while treatment targeting EGFR only could not sufficient to repress NFκB and STAT3 pathways for lung cancers harboring mutant EGFR. Therefore, synergistic treatment of TPCA-1 with TKIs is potential to be a more effective strategy for cancers.
http://mct.aacrjournals.org/content/early/2014/01/08/1535-7163.MCT-13-0464.abstract 2014