IGF-1R inhibition induces schedule-dependent sensitization of human melanoma to temozolomide

• Published in: Oncotarget 2015-11, Vol.6 (37), p.39877-39890
• Main Authors: Ramcharan, Roger, Aleksic, Tamara, Kamdoum, Wilfride Petnga, Gao, Shan, Pfister, Sophia X, Tanner, Jordan, Bridges, Esther, Asher, Ruth, Watson, Amanda J, Margison, Geoffrey P, Woodcock, Mick, Repapi, Emmanouela, Li, Ji-Liang, Middleton, Mark R, Macaulay, Valentine M
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; Blotting, Western; Cell Line, Tumor; Cell Survival - drug effects; Dacarbazine - administration & dosage; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; DNA Breaks, Double-Stranded - drug effects; Drug Administration Schedule; Drug Resistance, Neoplasm - drug effects; Drug Synergism; G1 Phase Cell Cycle Checkpoints - drug effects; Humans; Imidazoles - administration & dosage; Imidazoles - pharmacology; Melanoma - drug therapy; Melanoma - genetics; Melanoma - metabolism; Mice, Inbred BALB C; Mice, Nude; Mutation; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Pyrazines - administration & dosage; Pyrazines - pharmacology; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, IGF Type 1 - metabolism; Research Paper; Survival Analysis; Temozolomide; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.5631

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.