title: Synergistic effect of pacritinib with erlotinib on JAK2-mediated resistance in epidermal gowth factor receptor mutation-positive non-small cell lung Cancer.
abstract: The combination effect of pacritinib, a novel JAK2/FLT3 inhibitor, with erlotinib, the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), on non-small cell lung cancer cells with EGFR activating mutations was investigated. The combination showed synergistic effects on JAK2-mediated EGFR TKI-resistant PC-9/ER3 cells in some cases. The combination markedly suppressed pAKT and pERK although pSTAT3 expression was similar regardless of treatment with the pacritinib, pacritinib + erlotinib, or control in PC-9/ER3 cells. Receptor tyrosine kinase array profiling demonstrated that pacritinib suppressed MET in the PC-9/ER3 cells. The combined treatment of pacritinib and erlotinib in PC-9/ER3 xenografts showed more tumor shrinkage compared with each drug as monotherapy. Western blotting revealed that pMET in tumor samples was inhibited. These results suggest MET suppression by pacritinib may play a role in overcoming the EGFR-TKI resistance mediated by JAK2 in the PC-9/ER3 cells. In conclusion, pacritinib combined with EGFR-TKI might be a potent strategy against JAK2-mediated EGFR-TKI resistance.
authors.affiliation: Department of General Internal Medicine 4, Kawasaki Hospital, Kawasaki Medical School, Okayama 700-8505, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Ochi
authors.affiliation: Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Hideko
authors.initials: H
authors.lastname: Isozaki
authors.affiliation: Department of General Internal Medicine 4, Kawasaki Hospital, Kawasaki Medical School, Okayama 700-8505, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Takeyama
authors.affiliation: Head Translational Research and Medical Affairs, CTI Biopharma, Seattle, WA, USA.
authors.forename: Jack W
authors.initials: JW
authors.lastname: Singer
authors.affiliation: Department of General Internal Medicine 4, Kawasaki Hospital, Kawasaki Medical School, Okayama 700-8505, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Yamane
authors.affiliation: Department of General Internal Medicine 4, Kawasaki Hospital, Kawasaki Medical School, Okayama 700-8505, Japan; Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Honda
authors.affiliation: Department of Respiratory Medicine, Okayama University Hospital, Okayama 700-8558, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kiura
authors.affiliation: Department of General Internal Medicine 4, Kawasaki Hospital, Kawasaki Medical School, Okayama 700-8505, Japan. Electronic address: ntakigaw@gmail.com.
authors.forename: Nagio
authors.initials: N
authors.lastname: Takigawa
mesh_terms: D000818:Animals; D001952:Bridged-Ring Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy*; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: C561234:11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene; D001952:Bridged-Ring Compounds; D011743:Pyrimidines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D053614:Janus Kinase 2
keywords: EGFR; Erlotinib; JAK2; Lung cancer; Pacritinib; Resistance