title: Treatment effect of buparlisib, cetuximab and irradiation in wild-type or PI3KCA-mutated head and neck cancer cell lines.
abstract: Introduction In complement to anti-EGFR therapy, the targeting of PI3K/AKT/mTOR signaling pathway is of particular interest in the management of Head and Neck Squamous Cell Carcinoma (HNSCC). Here, we assess the effects of PI3K inhibition combined with anti-EGFR monoclonal antibody cetuximab and/or irradiation (RT). Material and methods Anti-proliferative effects of the combination of buparlisib (a specific PI3K inhibitor), cetuximab and RT was determined in two HNSCC cell lines (CAL33, PI3KCA H1047R-mutated and CAL27, PI3KCA wild-type). We examined biochemical factors related to proliferation, apoptosis (caspases), DNA repair (ERCC1, XRCC1) and the PI3K pathway (pEGFR/EGFR, pAKT/AKT, p-p70, p4EBP1). Results The best synergistic combined treatment in inhibiting cell proliferation was sequence 2 (cetuximab followed by buparlisib) in both cell lines. Addition of RT increased sequence 2 anti-proliferative effect only in CAL27. Data on protein expression indicated a possible activation of mTORC2 complex and caspases proteins in CAL27 not seen in CAL33. In CAL33, the synergistic anti-proliferative effect of the two drugs may derive from the higher sensitivity of mutated cells to PI3K targeting. Conclusions Our study demonstrates a synergistic effect of cetuximab followed by buparlisib in both PI3KCA wild-type and mutated cells, even with different intracellular signaling cross-talk depending on mutational status.
authors.affiliation: Laboratory of Cancer Genetics and Translational Oncology, Oncology Department, S. Croce University Hospital, Via Carle 25, 12100, Cuneo, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Lattanzio
authors.forename: Federica
authors.initials: F
authors.lastname: Tonissi
authors.forename: Martino
authors.initials: M
authors.lastname: Monteverde
authors.forename: Daniela
authors.initials: D
authors.lastname: Vivenza
authors.forename: Elvio
authors.initials: E
authors.lastname: Russi
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
authors.forename: Marco
authors.initials: M
authors.lastname: Merlano
authors.forename: Cristiana
authors.initials: C
authors.lastname: Lo Nigro
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000068818:Cetuximab / Q000494:pharmacology*; D059248:Chemoradiotherapy / Q000379:methods; D004260:DNA Repair / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D009025:Morpholines / Q000494:pharmacology*; D046912:Multiprotein Complexes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D000068818:Cetuximab; D066246:ErbB Receptors; D000076225:Mechanistic Target of Rapamycin Complex 2; D009025:Morpholines; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; C571178:NVP-BKM120; C546842:MTOR protein, human