TGF-β is produced excessively by many solid
tumors and can drive malignant progression through multiple effects on the
tumor cell and microenvironment. TGF-β signaling pathway inhibitors have shown efficacy in preclinical models of metastatic
cancer. Here, we investigated the effect of systemic
LY2109761, a TGF-β type I/II receptor (TβRI/TβRII)
kinase inhibitor, in both a
tumor allograft model and the mouse skin model of de novo chemically induced
carcinogenesis in vivo. Systemic
LY2109761 administration disrupted
tumor vascular architecture and reduced myofibroblast differentiation of E4 skin
carcinoma cells in a
tumor allograft. In the 7,12-dimethyl-benzanthracene plus
phorbol myristate acetate-induced skin chemical
carcinogenesis model, acute dosing of established naive primary
carcinomas with
LY2109761 (100 mg/kg) every 8 hours for 10 days (100 mg/kg) diminished phospho-Smad2 (P-Smad2) levels and marginally decreased the expression of inflammatory and invasive markers. Sustained exposure to
LY2109761 (100 mg/kg/d) throughout the
tumor outgrowth phase had no effect on
carcinoma latency or incidence. However, molecular analysis of resultant
carcinomas by microarray gene expression, Western blotting, and immunohistochemistry suggests that long-term
LY2109761 exposure leads to the outgrowth of
carcinomas with elevated P-Smad2 levels that do not respond to
drug. This is the first description of acquired resistance to a small-molecule inhibitor of the TβRI/TβRII
kinase. Resultant
carcinomas were more aggressive and inflammatory in nature, with delocalized
E-cadherin and elevated expression of Il23a,
laminin V, and
matrix metalloproteinases. Therefore, TGF-β inhibitors might be clinically useful for applications requiring acute administration, but long-term patient exposure to such drugs should be undertaken with caution.