Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been found to be effective against lung cancer in vitro, but clinical resistance to these agents has developed as their usage has increased. In this study, we determined whether the insulin-like growth factor I (IGF-I) signaling pathway induces resistance of non–small cell lung cancer (NSCLC) cells to the EGFR tyrosine kinase inhibitor gefitinib. Experimental Design: The effects of gefitinib and cetuximab on NSCLC cells, alone or with an IGF-I receptor (IGF-IR) inhibitor, were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, the flow cytometry–based terminal nucleotidyl transferase–mediated nick end labeling assay, coimmunoprecipitation, and Western blot analysis. EGFR and IGFR expression in NSCLC tissues were examined by Western blot analysis. Results: Gefitinib inhibited NSCLC cell proliferation by inducing apoptosis when IGF-IR signaling was suppressed. Treatment with gefitinib, but not cetuximab, induced EGFR:IGF-IR heterodimerization and activation of IGF-IR and its downstream signaling mediators, resulting in increased survivin expression in NSCLC cell lines with high levels of IGF-IR expression. Inhibition of IGF-IR activation and knockdown of survivin expression led to increased apoptosis. In contrast, overexpression of survivin protected cells with low IGF-IR expression from gefitinib-induced apoptosis. Most NSCLC tissues with EGFR overexpression had associated high levels of IGF-IR expression. Conclusions: IGF-IR expression may be useful as a predictive marker for gefitinib treatment of NSCLC. Suppression of IGF-IR signaling pathways may prevent or delay development of gefitinib resistance in patients with NSCLC.

Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling has been implicated in several human neoplasms. However, the role of serum levels of IGFs in lung cancer risk is controversial. We assessed the role of tissue-derived IGFs in lung carcinogenesis. We found that IGF-I and IGF-II levels in bronchial tissue specimens containing high-grade dysplasia were significantly higher than in those containing normal epithelium, hyperplasia, and squamous metaplasia. Derivatives of human bronchial epithelial cell lines with activation mutation in KRAS(V12) or loss of p53 overexpressed IGF-I and IGF-II. The transformed characteristics of these cells were significantly suppressed by inactivation of IGF-IR or inhibition of IGF-I or IGF-II expression but enhanced by overexpression of IGF-IR or exposure to the tobacco carcinogens (TC) 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone and benzo(a)pyrene. We further determined the role of IGF-IR signaling in lung tumorigenesis by determining the antitumor activities of the selective IGF-IR tyrosine kinase inhibitor cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo [1,5-a]pyrazin-8-ylamine using an in vitro progressive cell system and an in vivo mouse model with a lung-specific IGF

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These results indicate that downregulation of CaSR, and a higher rate of proliferation over apoptosis, could contribute to the pathological progression of SHPT.

Objective: The aim of this study was to ascertain whether all cervical cancer patients who received adjuvant concurrent chemoradiation (CCRT) for high risk of treatment failure after radical hysterectomy are at the same risk of treatment failure, and if not, to propose trial treatment modification. Methods: Between January 1999 and December 2007, 58 patients with FIGO stage Ib-IIa cervical cancer received adjuvant CCRT due to high risk factors such as positive lymph nodes or positive parametrium, or positive vaginal resection margins. Patients were divided into two Groups. Group A were patients with negative parametrium, negative vaginal resection margins, and only unilateral lymph node metastasis (involved L/N≤2). Group B were those with either bilateral pelvic lymph node involvement, or more than 2 lymph node involvement, or positive parametrium with lymph node involvement. Results: During a median follow-up period of 34 months (range, 6 to 102 months), 9 patients (15.5%) experienced recurrence; among whom 2 patients (2/28, 7.1%) were Group A, and 7 patients (7/30, 23.3%) were Group B. At 3 years, the estimated progression-free survival rate of all 58 patients was 78.3%, and the overall survival rate was 89.7%. Patients in Group A had significantly better progression-free survival (88.2% vs. 68.2%, p=0.042) and overall survival rate (100% vs. 78.8%, p=0.034) than Group B. Conclusion: Treatment modifications such as consolidation chemotherapy after CCRT may be considered based on the poor prognosis of very high risk patients such as those patients in Group B.