InsR uninhibited could overcome any positive effects of IGFR inhibition. Indeed, a recent study by Buck et al . has revealed that anti-IGFR antibody treatment resulted in a compensatory increase in phos- phorylation of InsR, which was associated with fesoterodine resistance to inhibition of IRS and AKT. While OSI-906 treatment resulted in an enhanced reduction of downstream signaling pathways 9 . Second, host toxicity, particularly hyper- glycemia, due to the metabolic effects of the monoclonal antibody could affect response to cytotoxic chemotherapy. Given the long half-life of antibodies, it would be difficult to reduce this toxic effect with this class of drugs.

Finally, as we have outlined, sequencing of the cytotoxic insult with anti-IGFR inhibition may be important. Our data suggest that the cytotoxic agent should precede IGFR/InsR inhi- bition. Again, the long half-life of monoclonal antibodies makes it difficult to achieve this sequencing. In this respect, the TKIs could be more effective in combination with Gemcitabine chemotherapy because of their pharmacokinetic properties. Further clinical development of these agents should focus on appropriate sequencing and scheduling to determine the benefit of these drug combinations. Acknowledgments We thank Dr. Do-Hyung Kim for constructive technical advice on autophagy experiments. We thank Dr. Elizabeth Buck from OSI Pharmaceuticals for providing OSI-906 and valuable 8 Breast Cancer Res Treat discussions in the writing of the manuscript. This work was supported by National Institutes of Health R0CA7485 to DY and National Cancer Institute Cancer Center Support Grant P30077598. 6.

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