title: In VitroandIn VivoSynergistic Antitumor Activity of the Combination of BKM120 and Erlotinib in Head and Neck Cancer: Mechanism of Apoptosis and Resistance.
abstract: We previously reported that the EGFR-targeted inhibitor erlotinib induces G1arrest of squamous cell carcinoma of the head and neck (SCCHN) cell lines without inducing significant apoptosis. Large-scale genomic studies suggest that >50% of SCCHN cases have activation of PI3K pathways. This study investigated whether cotargeting of EGFR and PI3K has synergistic antitumor effects and apoptosis induction. We examined growth suppression, apoptosis, and signaling pathway modulation resulting from single and combined targeting of EGFR and PI3K with erlotinib and BKM120, respectively, in a panel of SCCHN cell lines and a xenograft model of SCCHN. In a panel of 12 cell lines, single targeting of EGFR with erlotinib or PI3K with BKM120 suppressed cellular growth without inducing significant apoptosis. Cotargeting of EGFR and PI3K synergistically inhibited SCCHN cell line and xenograft tumor growth, but induced variable apoptosis; some lines were highly sensitive, others were resistant. Mechanistic studies revealed that the combination inhibited both axes of the mTORC1 (S6 and 4EBP1) pathway in apoptosis-sensitive cell lines along with translational inhibition of Bcl-2, Bcl-xL, and Mcl-1, but failed to inhibit p-4EBP1, Bcl-2, Bcl-xL, and Mcl-1 in an apoptosis-resistant cell line. siRNA-mediated knockdown of eIF4E inhibited Bcl-2 and Mcl-1 and sensitized this cell line to apoptosis. Our results strongly suggest that cotargeting of EGFR and PI3K is synergistic and induces apoptosis of SCCHN cell lines by inhibiting both axes of the AKT-mTOR pathway and translational regulation of antiapoptotic Bcl-2 proteins. These findings may guide the development of clinical trials using this combination of agents.Mol Cancer Ther; 16(4); 729-38. ©2017 AACR.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Abu Syed Md
authors.initials: AS
authors.lastname: Anisuzzaman
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Abedul
authors.initials: A
authors.lastname: Haque
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Mohammad Aminur
authors.initials: MA
authors.lastname: Rahman
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia.
authors.forename: Zhengjia
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Zhuo Georgia
authors.initials: ZG
authors.lastname: Chen
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia. aamin9@emory.edu.
authors.forename: A R M Ruhul
authors.initials: AR
authors.lastname: Amin
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D009025:Morpholines; C571178:NVP-BKM120; D000069347:Erlotinib Hydrochloride; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases