title: IGF-1R targeting increases the antitumor effects of DNA-damaging agents in SCLC model: an opportunity to increase the efficacy of standard therapy.
abstract: Insulin-like growth factor receptor-1 (IGF-1R) inhibition could be a relevant therapeutic approach in small cell lung cancer (SCLC) given the importance of an IGF-1R autocrine loop and its role in DNA damage repair processes. We assessed IGF-1R and pAkt protein expression in 83 SCLC human specimens. The efficacy of R1507 (a monoclonal antibody directed against IGF-1R) alone or combined with cisplatin or ionizing radiation (IR) was evaluated in H69, H146, and H526 cells in vitro and in vivo. Innovative genomic and functional approaches were conducted to analyze the molecular behavior under the different treatment conditions. A total of 53% and 37% of human specimens expressed IGF-1R and pAkt, respectively. R1507 showed single-agent activity in H146 and H526 cells but not in H69 cells. R1507 exhibited synergistic effects with both cisplatin and IR in vitro. The triple combination R1507-cisplatin-IR led to a dramatic delay in tumor growth compared with cisplatin-IR in H526 cells. Analyzing the apparent absence of antitumoral effect of R1507 alone in vivo, we observed a transient reduction of IGF-1R staining intensity in vivo, concomitant to the activation of multiple cell surface receptors and intracellular proteins involved in proliferation, angiogenesis, and survival. Finally, we identified that the nucleotide excision repair pathway was mediated after exposure to R1507-CDDP and R1507-IR in vitro and in vivo. In conclusion, adding R1507 to the current standard cisplatin-IR doublet reveals remarkable chemo- and radiosensitizing effects in selected SCLC models and warrants to be investigated in the clinical setting.
authors: INSERM U1030, Villejuif, France.
authors: Charles
authors: C
authors: Ferté
authors: Yohann
authors: Y
authors: Loriot
authors: Céline
authors: C
authors: Clémenson
authors: Frederic
authors: F
authors: Commo
authors: Andrea
authors: A
authors: Gombos
authors: Jean-Emmanuel
authors: JE
authors: Bibault
authors: Ingrid
authors: I
authors: Fumagalli
authors: Saad
authors: S
authors: Hamama
authors: Nathalie
authors: N
authors: Auger
authors: Benoit
authors: B
authors: Lahon
authors: Cyrus
authors: C
authors: Chargari
authors: Julien
authors: J
authors: Calderaro
authors: Jean-Charles
authors: JC
authors: Soria
authors: Eric
authors: E
authors: Deutsch
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004249:DNA Damage; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin; C551399:teprotumumab
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