Abstract 1253: Inhibition of FN14 to suppress KRAS-driven lung cancer migration and survival
| Autor: | Vashti M. Carson, Landon J. Inge, Seungchan Kim, Timothy G. Whitsett |
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| Rok vydání: | 2016 |
| Předmět: | |
| Zdroj: | Cancer Research. 76:1253-1253 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Lung cancer remains the leading cause of cancer related mortality throughout the world, and is estimated to kill more than one million people this year. Mutations in KRAS occur in about 1/3 of all lung adenocarcinomas, the most common histologic subtype of lung cancer. Mutations in KRAS are correlated with poor patient prognosis, advanced disease, therapeutic resistance and metastatic outcomes. There is an unmet clinical need to target KRAS-driven NSCLC towards abating the high mortality rate of this disease. We hypothesize that the tumor necrosis factor receptor, FN14 is induced and sustained by mutant KRAS signaling, and represents a therapeutic target in KRAS-driven NSCLC. Employing The Cancer Genome Atlas (TCGA) data, we showed that within a subgroup of adenocarcinoma patients harboring mutant KRAS, elevated FN14 expression conferred significantly worse survival outcomes compared to those with lower FN14 expression. Alone, elevated expression of FN14 conferred a poor prognosis in adenocarcinoma patients compared to lower expression of FN14. In lung cancer cell lines driven by mutant KRAS, elevated FN14 protein expression was observed. The ectopic induction of mutant KRAS in normal rat lung epithelial cells was sufficient to induce FN14 protein expression, an induction dependent on ERK signaling. In an animal model of mutant KRAS-driven NSCLC, FN14 protein was highly expressed and correlated with metastasis in vivo. TWEAK, the only known ligand for FN14, induced migration in NSCLC cell lines harboring mutant KRAS. Conversely, depletion of FN14 expression through siRNA suppressed KRAS-driven cell migration in vitro. We further demonstrated using a clonogenic assay that depletion of FN14 by siRNA was sufficient to reduce KRAS-driven NSCLC cell survival and significantly enhanced the cell killing effects of standard-of-care treatments such as radiation or cisplatin. These data suggest that NSCLC tumors harboring mutant KRAS may be vulnerable to inhibition of FN14 signaling. The recent development of FN14-targeted therapeutics provides an avenue towards clinical utility. As no therapeutics exist to target KRAS directly, a therapeutic strategy targeting FN14 might impact survival in KRAS-driven tumors and reduce the high mortality rate in this subgroup. Citation Format: Vashti M. Carson, Seungchan Kim, Landon J. Inge, Timothy G. Whitsett. Inhibition of FN14 to suppress KRAS-driven lung cancer migration and survival. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1253. |
| Databáze: | OpenAIRE |
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