Abstract

<div>Abstract<p><b>Purpose:</b> Anticancer drug development is inefficient, but genetically engineered murine models (GEMM) and orthotopic, syngeneic transplants (OST) of cancer may offer advantages to <i>in vitro</i> and xenograft systems.</p><p><b>Experimental Design:</b> We assessed the activity of 16 treatment regimens in a RAS-driven, <i>Ink4a/Arf</i>-deficient melanoma GEMM. In addition, we tested a subset of treatment regimens in three breast cancer models representing distinct breast cancer subtypes: claudin-low (<i>T11</i> OST), basal-like (<i>C3-TAg</i> GEMM), and luminal B (<i>MMTV-Neu</i> GEMM).</p><p><b>Results:</b> Like human RAS-mutant melanoma, the melanoma GEMM was refractory to chemotherapy and single-agent small molecule therapies. Combined treatment with AZD6244 [mitogen-activated protein–extracellular signal-regulated kinase kinase (MEK) inhibitor] and BEZ235 [dual phosphoinositide-3 kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor] was the only treatment regimen to exhibit significant antitumor activity, showed by marked tumor regression and improved survival. Given the surprising activity of the “AZD/BEZ” combination in the melanoma GEMM, we next tested this regimen in the “claudin-low” breast cancer model that shares gene expression features with melanoma. The AZD/BEZ regimen also exhibited significant activity in this model, leading us to testing in even more diverse GEMMs of basal-like and luminal breast cancer. The AZD/BEZ combination was highly active in these distinct breast cancer models, showing equal or greater efficacy compared with any other regimen tested in studies of over 700 tumor-bearing mice. This regimen even exhibited activity in lapatinib-resistant HER2<sup>+</sup> tumors.</p><p><b>Conclusion:</b> These results show the use of credentialed murine models for large-scale efficacy testing of diverse anticancer regimens and predict that combinations of PI3K/mTOR and MEK inhibitors will show antitumor activity in a wide range of human malignancies. <i>Clin Cancer Res; 18(19); 5290–303. ©2012 AACR</i>.</p></div>

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