Inhibition of c-Kit is not required for reversal of hyperglycemia by imatinib in NOD mice.
OBJECTIVE
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.


METHODS
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.


RESULTS
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
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.
JDRF Pharmacology, Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America.
Janet
J
Lau
Genetics and Neglected Diseases, Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America.
Qiang
Q
Zhou
Immunology Discovery, Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America.
Susan E
SE
Sutton
JDRF Pharmacology, Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America.
Ann E
AE
Herman
Genetics and Neglected Diseases, Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America.
Christian
C
Schmedt
Genetics and Neglected Diseases, Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America.
Richard
R
Glynne
D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D005260:Female; D006943:Hyperglycemia / Q000188:drug therapy* / Q000503:physiopathology; D000068877:Imatinib Mesylate; D051379:Mice; D016688:Mice, Inbred NOD; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D011743:Pyrimidines / Q000627:therapeutic use*
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit