Abstract 1886: Activation of IL-6R/JAK1/STAT3 signaling induces de novo resistance to irreversible EGFR inhibitors in non-small cell lung cancer with T790M resistance mutation

Abstract

Abstract Advanced non-small cell lung cancers (NSCLCs) with activating epidermal growth factor receptor (EGFR) mutation respond preferentially to reversible first-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib, but drug resistance invariably emerges. Acquisition of secondary T790M mutation in EGFR is the most common mechanism of acquired resistance to EGFR TKIs in these tumors. Although second-generation irreversible EGFR TKIs, such as BIBW2992 or PF00299804, have been introduced to overcome acquired resistance by the T790M mutation, showing they showed a limited clinical activity in patients with T790M mutant tumors. In this study, we first demonstrated in vitro and in vivo that JAK1-dependent STAT3 activation via autocrine IL-6 production was the key mechanism of de novo resistance to the irreversible EGFR TKIs in NSCLC cells harboring T790M mutation. Both BIBW2992 and PF00299804 induced STAT3 activation via JAK1, but not JAK2 or TYK2, and inhibition of JAK1/STAT3 signaling by small interfering RNA or pyridone 6 (P6, pan-JAK inhibitor) significantly increased sensitivity to BIBW2992 in H1975 or PC9-GR cells. BIBW2992-induced JAK1/STAT3 activation is mediated by interleukin-6 receptor (IL-6R) signaling pathway via autocrine IL-6 production. Cancer cells showed a stronger STAT3 activation and enhanced resistance to BIBW2992 in the presence of conditioned medium from MRC-5 (MRC5-CM) fibroblasts. Blocking of IL-6R/JAK1 signaling significantly inhibited MRC5-CM-induced STAT3 activation and increased the sensitivity to BIBW2992 in the presence of MRC5-CM, suggesting a critical role of IL-6R/JAK1/STAT3 signaling between fibroblasts and cancer cells in the development of drug resistance. Treatment of PC9-GR cells with BIBW2992 for 10 days in the presence of MRC5-CM significantly increased expression of several mesenchymal markers including snail, twist, vimentin, and N-cadherin. The epithelial-mesenchymal transition (EMT) upon short-term BIBW2992 treatment was not suppressed by the addition of P6, but was prevented by early concurrent administration of P6 with BIBW2992. In PC9-GR xenograft model, combination treatment with BIBW2992 and P6 showed a synergistic anti-tumor activity compared with BIBW2992 or P6 alone. Taken together, we suggest that inhibition of IL-6R/JAK1/STAT3 signaling can be a potential target to enhance therapeutic efficacy of irreversible EGFR TKIs in patients with a T790M resistance mutation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1886. doi:1538-7445.AM2012-1886