Synergistic effect of pacritinib with erlotinib on JAK2-mediated resistance in epidermal gowth factor receptor mutation-positive non-small cell lung Cancer

• Published in: Experimental cell research 2016-06, Vol.344 (2), p.194-200
• Main Authors: Ochi, Nobuaki, Isozaki, Hideko, Takeyama, Masami, Singer, Jack W., Yamane, Hiromichi, Honda, Yoshihiro, Kiura, Katsuyuki, Takigawa, Nagio
• Format: Article
• Language: English
• Subjects: Animals; Bridged-Ring Compounds - pharmacology; Bridged-Ring Compounds - therapeutic use; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Resistance, Neoplasm - drug effects; Drug Synergism; EGFR; Epidermal growth factor; Erlotinib; Erlotinib Hydrochloride - pharmacology; Erlotinib Hydrochloride - therapeutic use; Female; Humans; Inhibitor drugs; JAK2; Janus Kinase 2 - metabolism; Kinases; Lung cancer; Lung Neoplasms - drug therapy; Mice, SCID; Mutation; Mutation - genetics; Pacritinib; Phosphorylation - drug effects; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Receptor, Epidermal Growth Factor - genetics; Resistance; Xenograft Model Antitumor Assays
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2016.05.008

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. •A novel JAK2 inhibitor for EGFR mutation-positive lung cancer cells was investigated.•Pacritinib with erlotinib may be effective for JAK2-mediated EGFR-TKI resistance.•Suppressing MET with pacritinib may contribute this mechanism.