IGF-1R inhibition induces schedule-dependent sensitization of human melanoma to temozolomide.
dc.contributor.author | Ramcharan, R | en |
dc.contributor.author | Aleksic, T | en |
dc.contributor.author | Kamdoum, WP | en |
dc.contributor.author | Gao, S | en |
dc.contributor.author | Pfister, SX | en |
dc.contributor.author | Tanner, J | en |
dc.contributor.author | Bridges, E | en |
dc.contributor.author | Asher, R | en |
dc.contributor.author | Watson, AJ | en |
dc.contributor.author | Margison, GP | en |
dc.contributor.author | Woodcock, M | en |
dc.contributor.author | Repapi, E | en |
dc.contributor.author | Li, J-L | en |
dc.contributor.author | Middleton, MR | en |
dc.contributor.author | Macaulay, VM | en |
dc.date.accessioned | 2017-11-29T12:31:57Z | |
dc.date.available | 2017-11-29T12:31:57Z | |
dc.date.issued | 2015-11-24 | en |
dc.identifier.uri | http://hdl.handle.net/10026.1/10343 | |
dc.description.abstract |
Prior studies implicate type 1 IGF receptor (IGF-1R) in mediating chemo-resistance. Here, we investigated whether IGF-1R influences response to temozolomide (TMZ), which generates DNA adducts that are removed by O6-methylguanine-DNA methyltransferase (MGMT), or persist causing replication-associated double-strand breaks (DSBs). Initial assessment in 10 melanoma cell lines revealed that TMZ resistance correlated with MGMT expression (r = 0.79, p = 0.009), and in MGMT-proficient cell lines, with phospho-IGF-1R (r = 0.81, p = 0.038), suggesting that TMZ resistance associates with IGF-1R activation. Next, effects of IGF-1R inhibitors (IGF-1Ri) AZ3801 and linsitinib (OSI-906) were tested on TMZ-sensitivity, cell cycle progression and DSB induction. IGF-1Ri sensitized BRAF wild-type and mutant melanoma cells to TMZ in vitro, an effect that was independent of MGMT. Cells harboring wild-type p53 were more sensitive to IGF-1Ri, and showed schedule-dependent chemo-sensitization that was most effective when IGF-1Ri followed TMZ. This sequence sensitized to clinically-achievable TMZ concentrations and enhanced TMZ-induced apoptosis. Simultaneous or prior IGF-1Ri caused less effective chemo-sensitization, associated with increased G1 population and reduced accumulation of TMZ-induced DSBs. Clinically relevant sequential (TMZ → IGF-1Ri) treatment was tested in mice bearing A375M (V600E BRAF, wild-type p53) melanoma xenografts, achieving peak plasma/tumor IGF-1Ri levels comparable to clinical Cmax, and inducing extensive intratumoral apoptosis. TMZ or IGF-1Ri caused minor inhibition of tumor growth (gradient reduction 13%, 25% respectively), while combination treatment caused supra-additive growth delay (72%) that was significantly different from control (p < 0.01), TMZ (p < 0.01) and IGF-1Ri (p < 0.05) groups. These data highlight the importance of scheduling when combining IGF-1Ri and other targeted agents with drugs that induce replication-associated DNA damage. | en |
dc.format.extent | 39877 - 39890 | en |
dc.language | eng | en |
dc.language.iso | eng | en |
dc.subject | IGF-1R | en |
dc.subject | apoptosis | en |
dc.subject | chemo-sensitization | en |
dc.subject | double strand break | en |
dc.subject | temozolomide | en |
dc.subject | Animals | en |
dc.subject | Antineoplastic Combined Chemotherapy Protocols | en |
dc.subject | Apoptosis | en |
dc.subject | Blotting, Western | en |
dc.subject | Cell Line, Tumor | en |
dc.subject | Cell Survival | en |
dc.subject | DNA Breaks, Double-Stranded | en |
dc.subject | Dacarbazine | en |
dc.subject | Drug Administration Schedule | en |
dc.subject | Drug Resistance, Neoplasm | en |
dc.subject | Drug Synergism | en |
dc.subject | G1 Phase Cell Cycle Checkpoints | en |
dc.subject | Humans | en |
dc.subject | Imidazoles | en |
dc.subject | Melanoma | en |
dc.subject | Mice, Inbred BALB C | en |
dc.subject | Mice, Nude | en |
dc.subject | Mutation | en |
dc.subject | Proto-Oncogene Proteins B-raf | en |
dc.subject | Pyrazines | en |
dc.subject | Receptor, IGF Type 1 | en |
dc.subject | Survival Analysis | en |
dc.subject | Temozolomide | en |
dc.subject | Tumor Suppressor Protein p53 | en |
dc.subject | Xenograft Model Antitumor Assays | en |
dc.title | IGF-1R inhibition induces schedule-dependent sensitization of human melanoma to temozolomide. | en |
dc.type | Journal Article | |
plymouth.author-url | https://www.ncbi.nlm.nih.gov/pubmed/26497996 | en |
plymouth.issue | 37 | en |
plymouth.volume | 6 | en |
plymouth.publication-status | Published | en |
plymouth.journal | Oncotarget | en |
dc.identifier.doi | 10.18632/oncotarget.5631 | en |
plymouth.organisational-group | /Plymouth | |
plymouth.organisational-group | /Plymouth/REF 2021 Researchers by UoA | |
plymouth.organisational-group | /Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine | |
plymouth.organisational-group | /Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine/UoA01 Clinical Medicine | |
dc.publisher.place | United States | en |
dcterms.dateAccepted | 2015-10-03 | en |
dc.identifier.eissn | 1949-2553 | en |
dc.rights.embargoperiod | Not known | en |
rioxxterms.versionofrecord | 10.18632/oncotarget.5631 | en |
rioxxterms.licenseref.uri | http://www.rioxx.net/licenses/all-rights-reserved | en |
rioxxterms.licenseref.startdate | 2015-11-24 | en |
rioxxterms.type | Journal Article/Review | en |