title: Targeting c-Met in melanoma: mechanism of resistance and efficacy of novel combinatorial inhibitor therapy.
abstract: Numerous tyrosine kinase inhibitors (TKIs) targeting c-Met are currently in clinical trials for several cancers. Their efficacy is limited due to the development of resistance. The present study aims to elucidate this mechanism of c-Met TKI resistance by investigating key mTOR and Wnt signaling proteins in melanoma cell lines resistant to SU11274, a c-Met TKI. Xenografts from RU melanoma cells treated with c-Met TKIs SU11274 and JNJ38877605 showed a 7- and 6-fold reduction in tumor size, respectively. Resistant cells displayed upregulation of phosphorylated c-Met, mTOR, p70S6Kinase, 4E-BP1, ERK, LRP6, and active β-catenin. In addition, GATA-6, a Wnt signaling regulator, was upregulated, and Axin, a negative regulator of the Wnt pathway, was downregulated in resistant cells. Modulation of these mTOR and Wnt pathway proteins was also prevented by combination treatment with SU11274, everolimus, an mTOR inhibitor, and XAV939, a Wnt inhibitor. Treatment with everolimus, resulted in 56% growth inhibition, and a triple combination of SU11274, everolimus and XAV939, resulted in 95% growth inhibition in RU cells. The V600E BRAF mutation was found to be positive only in MU cells. Combination treatment with a c-Met TKI and a BRAF inhibitor displayed a synergistic effect in reducing MU cell viability. These studies indicate activation of mTOR and Wnt signaling pathways in c-Met TKI resistant melanoma cells and suggest that concurrent targeting of c-Met, mTOR, and Wnt pathways and BRAF may improve efficacy over traditional TKI monotherapy in melanoma patients.
authors.affiliation: Department of Biomedical Sciences; University of Illinois College of Medicine; Rockford, IL USA.
authors.forename: Deven
authors.initials: D
authors.lastname: Etnyre
authors.affiliation: Department of Biomedical Sciences; University of Illinois College of Medicine; Rockford, IL USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Stone
authors.affiliation: Department of Biomedical Sciences; University of Illinois College of Medicine; Rockford, IL USA.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Fong
authors.affiliation: Department of Biomedical Sciences; University of Illinois College of Medicine; Rockford, IL USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Jacobs
authors.affiliation: Department of Biomedical Sciences; University of Illinois College of Medicine; Rockford, IL USA.
authors.forename: Srijayaprakash B
authors.initials: SB
authors.lastname: Uppada
authors.affiliation: Department of Biomedical Sciences; University of Illinois College of Medicine; Rockford, IL USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Botting
authors.affiliation: Department of Biomedical Sciences; University of Illinois College of Medicine; Rockford, IL USA.
authors.forename: Supriya
authors.initials: S
authors.lastname: Rajanna
authors.affiliation: Department of Biomedical Sciences; University of Illinois College of Medicine; Rockford, IL USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Moravec
authors.affiliation: Department of Biomedical Sciences; University of Illinois College of Medicine; Rockford, IL USA.
authors.forename: Manohar R
authors.initials: MR
authors.lastname: Shambannagari
authors.affiliation: Department of Biomedical Sciences; University of Illinois College of Medicine; Rockford, IL USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Crees
authors.affiliation: Department of Biomedical Sciences; University of Illinois College of Medicine; Rockford, IL USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Girard
authors.affiliation: Department of Biomedical Sciences; University of Illinois College of Medicine; Rockford, IL USA.
authors.forename: Ceyda
authors.initials: C
authors.lastname: Bertram
authors.affiliation: Department of Biomedical Sciences; University of Illinois College of Medicine; Rockford, IL USA.
authors.forename: Neelu
authors.initials: N
authors.lastname: Puri
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D000068338:Everolimus; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D064593:Heterografts; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000008:administration & dosage; D017434:Protein Structure, Tertiary; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage; D011724:Pyridazines / Q000008:administration & dosage; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D006575:Heterocyclic Compounds, 3-Ring; D007211:Indoles; C000599304:JNJ38877605; D010879:Piperazines; D011720:Pyrazoles; D011724:Pyridazines; D013449:Sulfonamides; C490675:WNT7B protein, human; D051153:Wnt Proteins; C544261:XAV939; D019382:Human Growth Hormone; D000068338:Everolimus; C546842:MTOR protein, human; D019859:Proto-Oncogene Proteins c-met; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: BRAF; SU11274; Wnt; c-Met; mTOR; melanoma; resistance