Lau Janet, Zhou Qiang, Sutton Susan E, Herman Ann E, Schmedt Christian, Glynne Richard
JDRF Pharmacology, Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America.
Genetics and Neglected Diseases, Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America.
PLoS One. 2014 Jan 15;9(1):e84900. doi: 10.1371/journal.pone.0084900. eCollection 2014.
AIM/HYPOTHESIS: Recent studies indicate that tyrosine kinase inhibitors, including imatinib, can reverse hyperglycemia in non-obese diabetic (NOD) mice, a model of type 1 diabetes (T1D). Imatinib inhibits c-Abl, c-Kit, and PDGFRs. Next-generation tyrosine kinase inhibitors for T1D treatment should maintain activities required for efficacy while sparing inhibition of targets that might otherwise lead to adverse events. In this study, we investigated the contribution of c-Kit inhibition by imatinib in reversal of hyperglycemia in NOD mice.
The T670I mutation in c-Kit, which confers imatinib resistance, was engineered into the mouse genome and bred onto the NOD background. Hematopoietic stem cells (HSCs) from NOD.c-Kit(T670I) mice and NOD.c-Kit(wt) littermates were expanded in the presence or absence of imatinib to verify imatinib resistance of the c-Kit(T670I) allele. Diabetic mice were treated with imatinib at the onset of hyperglycemia for three weeks, and blood glucose was monitored.
In vitro expansion of HSCs from NOD.c-Kit(wt) mice was sensitive to imatinib, while expansion of HSCs from NOD.c-Kit(T670I) mice was insensitive to imatinib. However, in vivo treatment with imatinib lowered blood glucose levels in both strains of mice.
CONCLUSIONS/INTERPRETATION: The HSC experiment confirmed that, in NOD.c-Kit(T670I) mice, c-Kit is resistant to imatinib. As both NOD.c-Kit(T670I) and NOD.c-Kit(wt) mice responded comparably to imatinib, c-Kit inhibition does not substantially contribute to the efficacy of imatinib in T1D. Thus, we conclude that inhibition of c-Kit is not required in next-generation tyrosine kinase inhibitors for T1D treatment, and may be selected against to improve the safety profile.
目的/假设：近期研究表明，包括伊马替尼在内的酪氨酸激酶抑制剂可逆转1型糖尿病（T1D）模型非肥胖糖尿病（NOD）小鼠的高血糖。伊马替尼可抑制c-Abl、c-Kit和血小板衍生生长因子受体（PDGFRs）。用于T1D治疗的下一代酪氨酸激酶抑制剂应在保持疗效所需活性的同时，避免抑制可能导致不良事件的靶点。在本研究中，我们调查了伊马替尼抑制c-Kit对NOD小鼠高血糖逆转的作用。
将赋予伊马替尼抗性的c-Kit基因T670I突变导入小鼠基因组，并培育至NOD背景。在有或没有伊马替尼的情况下，扩增NOD.c-Kit（T670I）小鼠和NOD.c-Kit（野生型）同窝小鼠的造血干细胞（HSC），以验证c-Kit（T670I）等位基因对伊马替尼的抗性。糖尿病小鼠在高血糖发作时用伊马替尼治疗三周，并监测血糖。
来自NOD.c-Kit（野生型）小鼠的HSC体外扩增对伊马替尼敏感，而来自NOD.c-Kit（T670I）小鼠的HSC扩增对伊马替尼不敏感。然而，伊马替尼体内治疗降低了两种品系小鼠的血糖水平。
结论/解读：HSC实验证实，在NOD.c-Kit（T670I）小鼠中，c-Kit对伊马替尼具有抗性。由于NOD.c-Kit（T670I）和NOD.c-Kit（野生型）小鼠对伊马替尼的反应相当，c-Kit抑制对伊马替尼在T1D中的疗效没有实质性贡献。因此，我们得出结论，下一代用于T1D治疗的酪氨酸激酶抑制剂不需要抑制c-Kit，并且可以选择避免抑制c-Kit以改善安全性。
