ß-Catenin overexpression is associated with gefitinib resistance in non-small cell lung cancer cells.

BACKGROUND: Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) presents great challenges in the treatment of non-small cell lung cancer (NSCLC) patients, while the mechanisms are still not well understood. The ß-catenin signaling pathway has been found to be associated with chemoresistance and can activate the EGFR and its downstream pathways. This study aimed to investigate the role of ß-catenin in acquired resistance to EGFR-TKIs in NSCLC cell lines. METHODS: The expression and transcriptional activity of ß-catenin were measured in both the NSCLC cell line PC9 and its sub-line PC9/AB(2) which has acquired resistance to gefitinib. Knockdown and overexpression of ß-catenin in the PC9/AB(2) and PC9 cells were performed. The cell survival rate and the activation of the EGFR and its downstream pathways were detected in the two cell lines after transfection. RESULTS: Nuclear translocation of ß-catenin was increased in the PC9/AB(2) cells and the baseline expression of members of the ß-catenin signaling pathway was also higher in the PC9/AB(2) cells. Knocking down the expression of ß-catenin increased the sensitivity of the PC9/AB(2) cells to gefitinib by blocking the activation of the EGFR downstream pathways, while ß-catenin overexpression improved PC9 cells resistance to gefitinib by enhancing the activation of the EGFR and its downstream signaling. CONCLUSION: ß-catenin plays an important role in acquired resistance to EGFR-TKIs in NSCLC cell lines and may be a potential therapeutic target for NSCLC patients who have failed to respond to targeted therapy.

Clinical characteristics and survival of lung cancer patients associated with multiple primary malignancies.

OBJECTIVES: To investigate the characteristics and survival of lung cancer patients with additional malignant primary cancers. METHODS: Records of lung cancer patients newly diagnosed in Shanghai Pulmonary Hospital between January 2000 and January 2010 were retrospectively reviewed. Patients with second primary lung cancer and those with lung cancer only were included for detailed analysis. RESULTS: Of 27642 newly diagnosed lung cancer patients, 283 patients (1.02%) suffered previous additional primary cancers. Compared with single primary lung cancer, patients with secondary lung cancer associated other primary cancers were more often women (female to male ratio 1:1.72 vs 1:2.58, P = 0.018), older (64.2 vs 60.5 years old, P<0.001), more squamous cell type (30.7% vs 20.5%, P = 0.004), less small cell (3.9% vs 15.5%, P<0.001) type, at earlier stages (17.7% vs 11.0% for stage I, P = 0.014), and more frequently with family history of cancers (7.8% vs 3.9%, P = 0.038). The most common previous primary cancers observed were colorectal (22.0%), breast (18.4%), gastric (14.4%) and larynx cancers (11.9%). Approximately 42.9% of patients were diagnosed with lung cancer 2 to 6 years after diagnosis of initial primary cancers. The survival of patients with secondary lung cancer associated other malignancies was not significantly different from those with single lung cancer (P = 0.491), while synchronous multiple primary malignancies showed worse prognosis compared with those with metachronous ones or single lung cancer (p = 0.012). CONCLUSION: The possibility of second primary lung cancer should always be considered during the follow-up of related cancer types, especially those with family history of cancers. Patients with secondary lung cancer associated other primary malignancies have non-inferior survival than those with single lung cancer.