title: 5-Fluorouracil preferentially sensitizes mutant KRAS non-small cell lung carcinoma cells to TRAIL-induced apoptosis.
abstract: Mutations in the KRAS gene are very common in non-small cell lung cancer (NSCLC), but effective therapies targeting KRAS have yet to be developed. Interest in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a potent inducer of cell death, has increased following the observation that TRAIL can selectively kill a wide variety of human cancer cells without killing normal cells both in vitro and in xenograft models. However, results from clinical trials of TRAIL-based therapy are disappointingly modest at best and many have demonstrated a lack of therapeutic benefit. Current research has focused on selecting a subpopulation of cancer patients who may benefit from TRAIL-based therapy and identifying best drugs to work with TRAIL. In the current study, we found that NSCLC cells with a KRAS mutation were highly sensitive to treatment with TRAIL and 5-fluorouracil (5FU). Compared with other chemotherapeutic agents, 5FU displayed the highest synergy with TRAIL in inducing apoptosis in mutant KRAS NSCLC cells. We also found that, on a mechanistic level, 5FU preferentially repressed survivin expression and induced expression of TRAIL death receptor 5 to sensitize NSCLC cells to TRAIL. The combination of low-dose 5FU and TRAIL strongly inhibited xenograft tumor growth in mice. Our results suggest that the combination of TRAIL and 5FU may be beneficial for patients with mutant KRAS NSCLC.
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, USA.
authors.forename: Haizhen
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, USA. Electronic address: xwwu@mdanderson.org.
authors.forename: Xiangwei
authors.initials: X
authors.lastname: Wu
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000964:Antimetabolites, Antineoplastic; C117307:KRAS protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; D016283:Proto-Oncogene Proteins p21(ras); D005472:Fluorouracil
keywords: 5-Fluorouracil; Apoptosis; Lung cancer; TRAIL