Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model

Toshi Murakami, Nagio Takigawa, Takashi Ninomiya, Nobuaki Ochi, Masaaki Yasugi, Yoshihiro Honda, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Mitsune Tanimoto, Katsuyuki Kiura

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Objective: STAT3 plays a vital role in inducing and maintaining a pro-carcinogenic inflammatory microenvironment and is reported to be a critical mediator of the oncogenic effects of EGFR mutations. STAT3 activation is mediated through JAK family kinases. We investigated the effect of the JAK1/2 inhibitor AZD1480 on lung tumors induced by an activating EGFR mutation. Materials and methods: Three EGFR tyrosine kinase inhibitor-resistant cell lines (RPC-9, PC-9/Van-R and PC-9/ER3) established from PC-9 harboring an EGFR exon19 deletion mutation were used. Growth inhibition was measured using an MTT assay. Effects of AZD1480 were also evaluated in the xenograft model and in the EGFR transgenic mice model. Protein expressions were assessed by immunoblotting and immunohistochemistry. Group differences were compared using Student's t-test. To evaluate the efficacy of AZD1480 on survival, AZD1480 or vehicle was administered orally from 7 weeks of age of the transgenic mice. Overall survival curves were calculated using the Kaplan-Meier method. Results: The sensitivities of resistant and parent cells to AZD1480 were similar in vitro. AZD1480 (30 or 50. mg/kg/day, per os) reduced angiogenesis and revealed significant tumor regression in a mouse xenograft model. Subsequently, the transgenic mice were treated with AZD1480 (30. mg/kg/day) or vehicle alone. The numbers of lung tumors (long axis exceeding 1. mm) in the AZD1480-treated group and control group were 0.37. ±. 0.18 and 2.25. ±. 0.53 (p<. 0.001), respectively. AZD1480 treatment suppressed pSTAT3, pJAK1, pJAK2 and angiogenesis. The median survival time in the AZD1480-treated group (217 days) was significantly greater than that in the control group (106 days) (log-rank test, p<. 0.0001). Conclusion: AZD1480 may be effective against lung tumors driven by an activating EGFR mutation.

Original languageEnglish
Pages (from-to)30-36
Number of pages7
JournalLung Cancer
Volume83
Issue number1
DOIs
Publication statusPublished - Jan 1 2014

Keywords

  • EGFR
  • JAK2
  • Lung cancer
  • Oncogene addiction
  • STAT3
  • Transgenic mice

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Fingerprint Dive into the research topics of 'Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model'. Together they form a unique fingerprint.

  • Cite this