Abstract 4675: Synergistic effect of pacritinib with erlotinib on JAK2-mediated resistance in epidermal growth factor receptor mutation-positive non-small cell lung cancer

Abstract

Abstract Patients with non-small cell lung cancer (NSCLC) harboring activating mutations in the epidermal growth factor receptor (EGFR) benefit from treatment with EGFR tyrosine kinase inhibitors (TKIs). However, almost all of the patients eventually develop resistance to EGFR-TKIs within approximately one year. The resistance mechanisms of EGFR-TKIs have not been fully elucidated. We previously established an erlotinib-resistant NSCLC cell line named PC-9/ER3 after continuously exposing PC-9 cells, which harbor an in-frame deletion in EGFR exon 19, to erlotinib. PC-9/ER3 cells were 136-fold more resistant to erlotinib than the parental cells. Although the PC-9/ER3 cells did not carry the T790M mutation or MET amplification and had similar levels of pSTAT3, pJAK2 increased in the resistant cells (Cancer Sci 103, 1795-802; 2012). Meanwhile, pacritinib is a novel macrocyclic pyrimidine-based JAK2/FLT3 inhibitor with clinical activity in patients with myelofibrosis and lymphoma, which will be used as a standard therapy for myelofibrosis. In this study, we evaluated the synergistic effect of pacritinib combined with erlotinib on JAK2-medatited EGFR-TKI resistant NSCLC. Drug sensitivity was determined using an MTT assay and the combination index was calculated according to the methods based on the median-effect analysis. The combination of pacritinib with erlotinib showed synergistic effects on JAK2-medated EGFR TKI-resistant PC-9/ER3 cells in some cases. Western blotting showed that the combination treatment markedly suppressed pAKT and pERK although pSTAT3 was equivalent regardless of treatment with the pacritinib, erlotinib, pacritinib plus 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 the 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. Citation Format: Nobuaki Ochi, Hideko Isozaki, Masami Takeyama, Jack W. Singer, Hiromichi Yamane, Yoshihiro Honda, Katsuyuki Kiura, Nagio Takigawa. Synergistic effect of pacritinib with erlotinib on JAK2-mediated resistance in epidermal growth factor receptor mutation-positive non-small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4675.