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Published on: August 11, 2017
Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model
Toshi Murakami1, Nagio Takigawa2, Takashi Ninomiya1
1Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
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 1mm) 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.
Insights
The JAK1/2 inhibitor AZD1480 significantly reduced lung tumors in mice with EGFR mutations. This treatment suppressed tumor growth and prolonged survival, suggesting its potential for treating EGFR-mutated lung cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Signal transducer and activator of transcription 3 (STAT3) promotes a pro-carcinogenic inflammatory microenvironment.
- STAT3 activation is mediated by Janus kinases (JAKs) and is critical for the oncogenic effects of epidermal growth factor receptor (EGFR) mutations.
- Targeting STAT3 signaling is a potential therapeutic strategy for EGFR-mutated cancers.
Purpose of the Study:
- To investigate the efficacy of the JAK1/2 inhibitor AZD1480 in preclinical models of lung tumors with activating EGFR mutations.
- To assess the impact of AZD1480 on tumor growth, angiogenesis, and survival.
Main Methods:
- In vitro studies using EGFR tyrosine kinase inhibitor-resistant cell lines.
- In vivo evaluation in a mouse xenograft model and an EGFR transgenic mice model.
- Assessment of protein expression (pSTAT3, pJAK1, pJAK2) and angiogenesis via immunoblotting and immunohistochemistry.
- Survival analysis using Kaplan-Meier method.
Main Results:
- AZD1480 demonstrated similar sensitivity in resistant and parent cell lines in vitro.
- Significant tumor regression and reduced angiogenesis were observed in a mouse xenograft model.
- In EGFR transgenic mice, AZD1480 treatment markedly reduced lung tumor burden (0.37 vs. 2.25 tumors) and suppressed pSTAT3, pJAK1, and pJAK2.
- AZD1480 significantly prolonged median survival (217 days vs. 106 days) compared to vehicle control.
Conclusions:
- AZD1480 effectively inhibits STAT3 signaling and reduces tumor growth in preclinical models of EGFR-mutated lung cancer.
- AZD1480 demonstrates significant anti-tumor activity and survival benefit, supporting its potential as a therapeutic agent for lung tumors driven by activating EGFR mutations.
