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EGF receptor (EGFR) kinase inhibitors, including gefitinib and erlotinib, exert potent therapeutic efficacy in non-small cell lung cancers harboring EGFR-activating mutations. However, most patients ultimately develop resistance to these drugs. Here, we report a novel mechanism of acquired resistance to EGFR tyrosine kinase inhibitors and the reversal of which could improve clinical outcomes. In erlotinib-resistant lung cancer cells harboring activating EGFR mutations that we established, there was increased expression of Src, integrin b1, a2, and a5 along with enhanced cell adhesion activity. Interestingly, RNAi-mediated silencing of integrin b1 restored erlotinib sensitivity and reduced activation of Src and Akt after erlotinib treatment. Furthermore, Src silencing inhibited Akt phosphorylation and cell growth, with this inhibitory effect further augmented by erlotinib treatment. Increased expression of integrin b1, a5, and/or a2 was also observed in refractory tumor samples from patients with lung cancer treated with erlotinib and/or gefitinib. Together, our findings identify the integrin b1/Src/Akt signaling pathway as a key mediator of acquired resistance to EGFR-targeted anticancer drugs. Cancer Res; 73(20); 6243-53. Ó2013 AACR.

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Y-box binding protein-1 (YB-1) plays pivotal roles in acquisition of global drug resistance and cell growth promotion through transcriptional activation of genes for both drug resistance and growth factor receptors. In this study, we investigated whether YB-1 is involved in regulation of the cell cycle and cell proliferation of human cancer cells. Treatment with YB-1 siRNA caused a marked suppression of cell proliferation and expression of a cell cycle related gene, CDC6 by cancer cells. Of cell cycle of cancer cells, S phase content was specifically reduced by knockdown of YB-1. The overexpression of CDC6 abrogated this inhibition of both cell proliferation and S phase entry. ChIP assay demonstrated that YB-1 binds to a Y-box located in the promoter region of the CDC6 gene. Expression of cyclin D1, CDK1 and CDK2 was also reduced with increased expression of p21(Cip1) and p16(INK4A) when treated with YB-1 siRNA. Furthermore, the nuclear YB-1 expression was significantly associated with the level of CDC6 nuclear expression in patients with breast cancer. In conclusion, YB-1 plays an important role in cell cycle progression at G1/S of human cancer cells. YB-1 thus could be a potent biomarker for tumour growth and cell cycle in its close association with CDC6.

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N-myc downstream regulated gene 1 (NDRG1)/Cap43 expression is a predictive marker of good prognosis in patients with pancreatic cancer as we reported previously. In this study, NDRG1/Cap43 decreased the expression of various chemoattractants, including CXC chemokines for inflammatory cells, and the recruitment of macrophages and neutrophils with suppression of both angiogenesis and growth in mouse xenograft models. We further found that NDRG1/Cap43 induced nuclear factor-κB (NF-κB) signaling attenuation through marked decreases in inhibitor of κB kinase (IKK) β expression and IκBα phosphorylation. Decreased IKKβ expression in cells overexpressing NDRG1/Cap43 resulted in reduction of both nuclear translocation of p65 and p50 and their binding to the NF-κB motif. The introduction of an exogenous IKKβ gene restored NDRG1/Cap43-suppressed expression of melanoma growth-stimulating activity α/CXCL1, epithelial-derived neutrophil activating protein-78/CXCL5, interleukin-8/CXCL8 and vascular endothelial growth factor-A, accompanied by increased phosphorylation of IκBα in NDRG1/Cap43-expressing cells. In patients with pancreatic cancer, NDRG1/Cap43 expression levels were also inversely correlated with the number of infiltrating macrophages in the tumor stroma. This study suggests a novel mechanism by which NDRG1/Cap43 modulates tumor angiogenesis/growth and infiltration of macrophages/neutrophils through attenuation of NF-κB signaling.

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