title: Enhanced Antitumor Activity of Cetuximab in Combination with the Jak Inhibitor CYT387 against Non-Small-Cell Lung Cancer with Various Genotypes.
abstract: Cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, is effective in the treatment of non-small-cell lung cancers (NSCLCs). However, resistance to EGFR inhibitors limits its effectiveness. In this study, we investigated the effectiveness of Jak-2 inhibitor, CYT387, in combination with cetuximab. Xenograft animal models were administered with cetuximab or CYT387 or their combination. It was observed that NSCLC cells exhibited enormous differences in responses to cetuximab; cell lines were more intrinsically resistant to cetuximab. In resistant cell lines (H1975 and H1650), the efficacy of cetuximab was increased when combined with CYT387, whereas CYT387 alone in low doses exhibited little effect on NSCLC cell proliferation. In addition, the antitumor activity of cetuximab was increased in H1975 resistant model in spite of low efficacy of cetuximab treatment alone in. Jak/STAT signaling was suppressed effectively by the combination of cetuximab and CYT387. In summary, our findings indicated that CYT387 has a potent indirect antitumor activity, and it is also synergistic in its activity in combination with cetuximab against NSCLC tumors, especially with cetuximab intrinsic-resistance tumors. These indications were mediated via Janus kinase (Jak)-signal transducer and transcription (STAT) pathway activator. Our results strongly and consistently supported the potential synergism of CYT387 as Jak inhibitor for anti-NSCLC therapy with EGFR-targeting agents.
authors.affiliation: Department of Clinical Pharmacology, Pharmacy Care Center, Chinese PLA General Hospital , Beijing 100853, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Clinical Pharmacology, Pharmacy Care Center, Chinese PLA General Hospital , Beijing 100853, China.
authors.forename: Xian-Zhe
authors.initials: XZ
authors.lastname: Dong
authors.affiliation: Department of Clinical Pharmacology, Pharmacy Care Center, Chinese PLA General Hospital , Beijing 100853, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, Pharmacy Care Center, Chinese PLA General Hospital , Beijing 100853, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and System Therapeutics, Mount Sinai School of Medicine ; New York, New York 10029, United States.
authors.forename: Yi-Bang
authors.initials: YB
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D011743:Pyrimidines; C546012:N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide; D053612:Janus Kinases; D000068818:Cetuximab
keywords: Jak/STAT; cetuximab; resistant