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Published on: October 6, 2014
Dual inhibition of epidermal growth factor and insulin-like 1 growth factor receptors reduce intestinal adenoma
P H S Shaw1, T S Maughan, A R Clarke
1School of Bioscience, Cardiff University, Museum Avenue, Cardiff CF10 3AX, Wales, UK.
Background:
Identification of early molecular pathway changes may be useful as biomarkers for tumour response/resistance prediction, and here we provide direct in vivo proof of this concept. The type 1 insulin-like growth factor receptor (IGF1R) has been implicated in various aspects of adenoma development and metastasis. We show here that, in murine intestinal adenomas acutely exposed to a small molecular inhibitor of EGFR (gefitinib), there is concurrent suppression of EGFR downstream signalling and induction of IGF signalling. We therefore tested the hypothesis that blockade of EGFR signalling was being tempered by compensatory activation of the IGF pathway by examining the effect of chronic suppression of IGF1R using AZ12253801, a small molecular tyrosine kinase inhibitor of IGF1R.
Methods:
Male Apc(min/+) mice with an intestinal tumour burden were exposed to a single dose of an inhibitor against EGFR (gefitinib), IGF1R (AZ12253801), 0.5% Tween 80 or combined EGFR/IGF1R inhibitor and culled 4 h post dosing. Tumour tissue was analysed to detect the early molecular pathways induced and anti-tumour phenotypic changes. Cohorts of male Apc(min/+) mice (n=15-17) were subsequently treated with gefitinib for a period of 8 weeks and subsequently exposed to single (either gefitinib or AZ12253801) or combined (gefitinib and AZ12253801) therapy. We also included a vehicle-treated cohort, which was never exposed to gefitinib and became symptomatic of the disease by day 150.
Results:
Both single treatments delayed the onset of disease symptoms. Combined dosing with gefitinib and AZ12253801 similarly delayed the onset of symptoms, and at 200 days suppressed small intestinal tumourigenesis more effectively than either treatment alone (median small intestinal adenoma volume (47 mm(3) (comb) vs 248 mm(3) (AZ12253801), P=0.0003 and 47 mm(3) (comb) vs 123 mm(3) (gefitinib), P=0.0042, Mann-Whitney (two-sided) test).
Conclusion:
Our data provide evidence in support of the use of combinatorial therapy, and establishes the need to further define the precise benefit in vivo.
Insights
Combining EGFR and IGF1R inhibitors in mice with intestinal adenomas delayed disease onset and suppressed tumor growth more effectively than single treatments. Further research is needed to define the precise in vivo benefits of this combinatorial therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Type 1 insulin-like growth factor receptor (IGF1R) is implicated in adenoma development and metastasis.
- EGFR inhibition in murine intestinal adenomas suppresses EGFR signaling and induces IGF signaling.
- Compensatory IGF pathway activation may temper EGFR blockade.
Purpose of the Study:
- To test if chronic suppression of IGF1R using AZ12253801 can overcome compensatory IGF pathway activation during EGFR inhibition.
- To evaluate the efficacy of combined EGFR and IGF1R inhibition in a murine intestinal adenoma model.
Main Methods:
- Apc(min/+) mice with intestinal tumors were treated with gefitinib (EGFR inhibitor), AZ12253801 (IGF1R inhibitor), or both.
- Tumor tissue was analyzed for molecular pathway changes and anti-tumor effects.
- Mice were treated for 8 weeks, with symptom onset and tumor burden assessed.
Main Results:
- Both single EGFR and IGF1R inhibition delayed disease symptom onset.
- Combined gefitinib and AZ12253801 treatment suppressed small intestinal tumorigenesis more effectively than either agent alone at 200 days.
- Median adenoma volume was significantly reduced in combined therapy groups compared to single-agent groups.
Conclusions:
- Data support the use of combinatorial therapy targeting EGFR and IGF1R.
- Further in vivo studies are required to precisely define the benefits of this combined therapeutic approach.
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