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Published on: October 27, 2020
Control of mammary tumor differentiation by SKI-606 (bosutinib)
1Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Abstract:
C-Src is infrequently mutated in human cancers but it mediates oncogenic signals of many activated growth factor receptors and thus remains a key target for cancer therapy. However, the broad function of Src in many cell types and processes requires evaluation of Src-targeted therapeutics within a normal developmental and immune-competent environment. In an effort to understand the appropriate clinical use of Src inhibitors, we tested an Src inhibitor, SKI-606 (bosutinib), in the MMTV-PyVmT transgenic mouse model of breast cancer. Tumor formation in this model is dependent on the presence of Src, but the necessity of Src kinase activity for tumor formation has not been determined. Furthermore, Src inhibitors have not been examined in an autochthonous tumor model that permits assessment of effects on different stages of tumor progression. Here we show that oral administration of SKI-606 inhibited the phosphorylation of Src in mammary tumors and caused a rapid decrease in the Ezh2 Polycomb group histone H3K27 methyltransferase and an increase in epithelial organization. SKI-606 prevented the appearance of palpable tumors in over 50% of the animals and stopped tumor growth in older animals with pre-existing tumors. These antitumor effects were accompanied by decreased cellular proliferation, altered tumor blood vessel organization and dramatically increased differentiation to lactational and epidermal cell fates. SKI-606 controls the development of mammary tumors by inducing differentiation.
Insights
Src kinase inhibitors, like bosutinib (SKI-606), can prevent and halt breast cancer progression by inducing tumor cell differentiation. This study evaluated bosutinib in a mouse model, showing significant antitumor effects.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- C-Src tyrosine kinase is crucial for oncogenic signaling in various cancers, making it a therapeutic target.
- Understanding Src inhibitor effects in vivo is vital for clinical application, necessitating studies in relevant models.
Purpose of the Study:
- To investigate the efficacy of the Src inhibitor SKI-606 (bosutinib) in a transgenic mouse model of breast cancer.
- To determine the impact of Src inhibition on tumor progression, differentiation, and associated molecular pathways.
Main Methods:
- Oral administration of SKI-606 to MMTV-PyVmT transgenic mice with or without pre-existing mammary tumors.
- Assessment of Src phosphorylation, Ezh2 activity, epithelial organization, tumor growth, proliferation, angiogenesis, and cell differentiation.
Main Results:
- SKI-606 inhibited Src phosphorylation and decreased Ezh2 methyltransferase activity in mammary tumors.
- Bosutinib prevented tumor formation in 50% of animals and halted growth in those with existing tumors.
- Antitumor effects included reduced proliferation, altered vasculature, and increased differentiation to lactational and epidermal fates.
Conclusions:
- SKI-606 effectively controls mammary tumor development by inducing differentiation.
- Src inhibition represents a promising therapeutic strategy for breast cancer, impacting multiple stages of tumor progression.
