title: Schedule-dependent interaction between temsirolimus and cetuximab in head and neck cancer: a preclinical study.
abstract: Aberrant epidermal growth factor receptor (EGFR) signaling is associated with tumor growth in head and neck squamous cell carcinoma (HNSCC) and is a major focus of targeted therapy. The phosphatidylinositol-3-kinase/AKT/mammalian target of the rapamycin (PI3K/AKT/mTOR) signaling pathway is frequently mutated in HNSCC and is involved in disease progression and resistance to EGFR inhibitors. The aim of this study was to assess the antiproliferative effects of mTOR inhibition (temsirolimus) combined with the anti-EGFR monoclonal antibody cetuximab, administered according to different combination schedules. Antiproliferative effects of the combination of temsirolimus and cetuximab were determined on the representative HNSCC CAL33 cell line (PI3KCA H1047R mutated and K-RAS wild-type). In addition, key proteins related to the EGFR pathway (pEGFR/EGFR, pAKT/AKT) and the mTOR pathway (p-p70S6K1, p4E-BP1) were determined to explain the cytotoxic effects. Temsirolimus and cetuximab showed a synergistic effect when administered in combination. Supra-additive effect was lost when the two drugs were administered sequentially, irrespective of which drug was administered first. Synergistic effect of the combination was corroborated by a marked downregulation of pEGFR, significant downregulation of pAKT expression, and a marked diminution of p70S6K1 and p4E-BP1 expression. Our study demonstrated a synergistic effect of temsirolimus and cetuximab administered in combination, well illustrated by a simultaneous blockade of intracellular signaling pathways regulating cell proliferation and survival. These results establish the notion of a schedule dependency for the combined treatment, which can be of importance at the clinical level.
authors.affiliation: aLaboratory of Cancer Genetics and Translational Oncology and Medical Oncology, Oncology Department, S. Croce and Carle Teaching Hospital, Cuneo, Italy bOncopharmacology Unit, Centre Antoine Lacassagne, Nice, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Lattanzio
authors.forename: Gerard
authors.initials: G
authors.lastname: Milano
authors.forename: Martino
authors.initials: M
authors.lastname: Monteverde
authors.forename: Federica
authors.initials: F
authors.lastname: Tonissi
authors.forename: Daniela
authors.initials: D
authors.lastname: Vivenza
authors.forename: Marco
authors.initials: M
authors.lastname: Merlano
authors.forename: Cristiana
authors.initials: C
authors.lastname: Lo Nigro
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000008:administration & dosage* / Q000494:pharmacology; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077195:Squamous Cell Carcinoma of Head and Neck; D018631:ras Proteins / Q000378:metabolism
chemical_list: C401859:temsirolimus; C512478:EGFR protein, human; D066246:ErbB Receptors; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins; D000068818:Cetuximab; D020123:Sirolimus