MAB391 down-regulated IGF 1R expression in MCF 7/LTED cells without affecting InsR levels. OSI 906 had no influence on receptor amounts but blocked ligand induced phosphorylation of InsR, pifithrin IGF 1R, and AKT. In comparison, MAB391 blocked IGF 1 induced activation of IGF 1R, slightly reduced IGF 1 induced P AKT, but had little influence on insulin action. OSI 906 was more efficient than MAB391 at preventing IGF 1 caused P AKT, along with basal P AKT and P S6 levels. These data suggest that in cells, InsR can retain PI3K signaling in the absence of IGF 1R. Treatment with OSI 906 however not MAB391 avoided or delayed the ZR75 1, HCC 1428, emergence of hormoneindependent MCF 7, and MDA 361 cells following estrogen deprivation. More, OSI 906 treatment prevented the power of insulin and IGF 1 to rescue MCF 7 cells from estrogen deprivation, while MAB391 prevented rescue just by IGF 1 but not by insulin. Significantly, OSI 906 stopped rescue by IGF Skin infection 1 better-than MAB391, though both drugs fully blocked IGF 1R phosphorylation. These suggest that blockade of InsR and IGF 1R is necessary to prevent resistance to estrogen deprivation, and that inhibition of IGF 1R alone is insufficient. Double InsR/IGF 1R blockade stops hormone independent cyst growth We next compared the antitumor activity in vivo of MAB391 and OSI 906. Ovariectomized tumor bearing rats were randomized to vehicle, OSI 906, MAB391, or even the combination. OSI 906 somewhat suppressed cyst growth in comparison with vehicle. Alternatively, MAB391 had no effect even though it markedly downregulated tumor IGF 1R levels. The drug combination did not further reduce cyst growth in comparison with OSI 906 alone. OSI 906 although not MAB391 reduced levels of G InsR/ IGF 1R as measured by IHC. Therapy with MAB391 and OSI 906 triggered 1, as shown with other IGF 1R antibodies and TKIs. 4 fold and 50 fold increases Foretinib solubility in serum insulin levels, respectively, C peptide levels were similarly altered. The antibody employed for IHC detects both phosphorylated InsR and IGF 1R, thus implying that tumor cells maintain InsR activation when treated with the IGF 1R antibody. This implies blockade of IGF 1R alone is insufficient to suppress hormone independent tumor growth. While we did not determine serum glucose levels, we must note transient and reversible hyperglycemia is seen in mice treated with OSI 906. Therapy with the ER downregulator fulvestrant is demonstrated to inhibit growth of MCF 7 cells and xenografts under estrogen depleted conditions. Others have shown that IGF 1R crosstalks with ER, and fulvestrant lowers IGF 1R and IRS 2 expression in MCF 7 cells in estrogen free conditions. Further, therapeutic inhibition of InsR/IGF 1R in patients with endocrine resistant breast cancer is going to be examined in combination with antiestrogens.