Most NSCLC patients with EGFR mutations benefit from treatment with EGFR-TKIs, but the clinical efficacy of EGFR-TKIs is limited by the appearance of drug resistance. Multiple kinase inhibitors of EGFR family proteins such as afatinib have been newly developed to overcome such drug resistance. We established afatinib-resistant cell lines after chronic exposure of activating EGFR mutation-positive PC9 cells to afatinib. Afatinib-resistant cells showed following specific characteristics as compared to PC9: [1] Expression of EGFR family proteins and their phosphorylated molecules was markedly downregulated by selection of afatinib resistance; [2] Expression of FGFR1 and its ligand FGF2 was alternatively upregulated; [3] Treatment with anti-FGF2 neutralizing antibody blocked enhanced phosphorylation of FGFR in resistant clone; [4] Both resistant clones showed collateral sensitivity to PD173074, a small-molecule FGFR-TKIs, and treatment with either PD173074 or FGFR siRNA exacerbated suppression of both afatinib-resistant Akt and Erk phosphorylation when combined with afatinib; [5] Expression of twist was markedly augmented in resistant sublines, and twist knockdown specifically suppressed FGFR expression and cell survival. Together, enhanced expression of FGFR1 and FGF2 thus plays as an escape mechanism for cell survival of afatinib-resistant cancer cells, that may compensate the loss of EGFR-driven signaling pathway.

Expression of excision repair cross‐complementation group 1 (ERCC1), p53, or thioredoxin (TRX) is reported to be correlated with resistance to platinum‐based drugs. The authors evaluated whether ERCC1, p53, or TRX expression could predict progression‐free and/or overall survival in relapsed non‐small cell lung cancer (NSCLC) patients treated with platinum‐based chemotherapy. Immunohistochemistry was used to examine the expression of these three proteins in resected lung tumor samples obtained from 67 patients treated with platinum‐based chemotherapy against recurrent tumors after curative resection. Immunostaining for ERCC1, p53, and TRX was positive in 29, 35, and 24 patients, respectively. Patients negative for ERCC1 had a significantly longer median progression‐free (44 vs 26 weeks, P = 0.0075) and overall (73 vs 44 weeks, P = 0.0006) survival than those positive for ERCC1. Patients negative for p53 expression had a significantly longer median overall (70 vs 62 weeks, P = 0.0289), but not progression‐free (37.5 vs 36 weeks, P = 0.2465), survival than those positive for p53 expression. From multivariate analysis, negative ERCC1 expression (hazard ratio [HR] = 1.3740, P = 0.0147) was a significantly favorable factor for progression‐free survival, and negative ERCC1 expression (HR = 1.6533, P = 0.0018) and better performance status (HR = 1.9117, P = 0.0017) were significantly favorable factors for overall survival. This retrospective study indicates that immunostaining for ERCC1 may be useful for predicting survival in NSCLC patients receiving platinum‐based chemotherapy against recurrent tumors after curative resection and can provide critical information for planning personalized chemotherapy. (Cancer Sci 2007; 98: 1336–1343)