IGF-1R inhibition induces schedule-dependent sensitization of human melanoma to temozolomide
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Roger Ramcharan1, Tamara Aleksic1, Wilfride Petnga Kamdoum1, Shan Gao1, Sophia X. Pfister1, Jordan Tanner2, Esther Bridges1, Ruth Asher3, Amanda J. Watson4, Geoffrey P. Margison4,*, Mick Woodcock1, Emmanouela Repapi5, Ji-Liang Li1, Mark R. Middleton6, Valentine M. Macaulay1,6
1Department of Oncology, Old Road Campus Research Building, Oxford, UK
2Biomedical Services, John Radcliffe Hospital, Oxford, UK
3Department of Pathology, John Radcliffe Hospital, Oxford, UK
4Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester, UK
5Computational Biology Research Group, Weatherall Institute of Molecular Medicine, Oxford, UK
6Oxford Cancer Centre, Churchill Hospital, Oxford, UK
*Present address: Centre for Occupational and Environmental Health, University of Manchester, Manchester, UK
Valentine M. Macaulay, e-mail: email@example.com
Keywords: IGF-1R, chemo-sensitization, double strand break, temozolomide, apoptosis
Received: August 19, 2015 Accepted: October 03, 2015 Published: October 15, 2015
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.
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