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

Nobuaki Ochi; Hideko Isozaki; Masami Takeyama; Jack W Singer; Hiromichi Yamane; Yoshihiro Honda; Katsuyuki Kiura; Nagio Takigawa

doi:10.1016/j.yexcr.2016.05.008

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

Exp Cell Res. 2016 Jun 10;344(2):194-200. doi: 10.1016/j.yexcr.2016.05.008. Epub 2016 May 11.

Authors

Nobuaki Ochi¹, Hideko Isozaki², Masami Takeyama¹, Jack W Singer³, Hiromichi Yamane¹, Yoshihiro Honda⁴, Katsuyuki Kiura⁵, Nagio Takigawa⁶

Affiliations

¹ Department of General Internal Medicine 4, Kawasaki Hospital, Kawasaki Medical School, Okayama 700-8505, Japan.
² Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
³ Head Translational Research and Medical Affairs, CTI Biopharma, Seattle, WA, USA.
⁴ 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.
⁵ Department of Respiratory Medicine, Okayama University Hospital, Okayama 700-8558, Japan.
⁶ Department of General Internal Medicine 4, Kawasaki Hospital, Kawasaki Medical School, Okayama 700-8505, Japan. Electronic address: ntakigaw@gmail.com.

PMID: 27180268
DOI: 10.1016/j.yexcr.2016.05.008

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.

Keywords: EGFR; Erlotinib; JAK2; Lung cancer; Pacritinib; Resistance.

MeSH terms

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
ErbB Receptors / genetics*
Erlotinib Hydrochloride / pharmacology
Erlotinib Hydrochloride / therapeutic use*
Female
Humans
Janus Kinase 2 / metabolism*
Lung Neoplasms / drug therapy*
Mice, SCID
Mutation / genetics*
Phosphorylation / drug effects
Pyrimidines / pharmacology
Pyrimidines / therapeutic use*
Xenograft Model Antitumor Assays

Substances

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
Bridged-Ring Compounds
Pyrimidines
Erlotinib Hydrochloride
ErbB Receptors
Janus Kinase 2