Outgrowth of Drug-Resistant Carcinomas Expressing Markers of Tumor Aggression after Long-term T RI/II Kinase Inhibition with LY2109761

Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94158, USA.
Cancer Research (Impact Factor: 9.33). 03/2011; 71(6):2339-49. DOI: 10.1158/0008-5472.CAN-10-2941
Source: PubMed


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.

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    • "Since only a few TGF-β inhibitors are currently being studied in clinical trials, the development of appropriate preclinical models is considered imperative in order to reliably establish the mechanisms of action of TGF-β inhibitors and to specifically direct new drug screens. In traditional models such as xenografts with established tumor cell lines or in vitro cell viability studies, galunisertib has shown moderate anti-tumor activity [10, 11]. Here, we used patient-derived xenografts (PDX) instead of established tumorderived cell lines [12, 13]. "
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    • "Four classes of TGF-β inhibiting molecules have already been tested in clinical trials, with responses that generally fell short of hopes (118). At least one class of TGF-β inhibitor has also shown the capacity to elicit biochemical resistance in mouse models (119). This observation, coupled with the integral roles of TGF-β in wound healing and tissue homeostasis, suggests that long-term inhibition of TGF-β signaling may be a dangerous prospect. "
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    • "Clearly the increasing understanding of TGFβ and its functions has brought a new era in molecular therapeutics. However, acquired resistance to small molecule inhibitors is a problem that has already manifested, with resultant carcinomas more aggressive and inflammatory [22]. The recent discovery that there is transcriptional talk between TGFβ and stem cell pathways holds more promising research to come [23]. "
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