Abstract
Lung cancer is the leading cause of cancer deaths in the USA and worldwide and ∼85% of these cancers are of the non-small cell lung cancer (NSCLC) subtype. Approximately 10-15% of the NSCLC patients in the USA and 30-50% of these patients in Asia have tumors harboring somatic mutations in the epidermal growth factor receptor (EGFR) that cause constitutive activation of this receptor. These patients have the best clinical response to the small molecule EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Here we report that the TNF receptor superfamily member fibroblast growth factor-inducible 14 (Fn14) is frequently overexpressed in NSCLC tumors. We have also found that NSCLC cell lines that contain the same EGFR activating mutations found in patients express high levels of Fn14. Erlotinib treatment of these cells decreases Fn14 levels; therefore, EGFR signaling is indeed triggering Fn14 gene expression in these cell lines. Consistent with this proposal, when EGFR activation mutant receptors (L858R, ΔL747-E749, and D770-N771 insertion) were expressed in rat RL65 lung epithelial cells Fn14 expression was induced. In contrast, RL65 cells expressing a kinase-deficient EGFR receptor (D837A) did not show an increase in Fn14 expression. Since some NSCLC tumors with EGFR activating mutations acquire an additional EGFR mutation (T790M) that promotes TKI resistance, we examined Fn14 levels in a cell line containing both types of mutations. The Fn14 receptor was expressed at high levels in these cells. Finally, we found that shRNA-mediated Fn14 knockdown reduces NSCLC cell migration. Together, these data indicate that EGFR activation in NSCLC cells increases Fn14 gene expression and that Fn14 levels remain elevated in drug resistant cells. Furthermore, Fn14 may play a role in NSCLC cell motility. We propose that Fn14 may be a good biomarker for selection of NSCLC patients most likely to benefit from EGFR TKIs. It may also be a therapeutic target for NSCLC patients; in particular, for those patients with EGFR-driven tumors who have either primary or acquired resistance to EGFR tyrosine kinase inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1216. doi:10.1158/1538-7445.AM2011-1216