P3-16-03: Enhancing Anti-IGF Directed Therapeutics by Co-Targeting Autophagy.

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Abstract Autophagy (macroautophagy) is a cellular mechanism that maintains homeostasis and cell growth by regulating the turnover of damaged proteins. Autophagy has a critical role in maintaining cellular viability during nutrient starvation and metabolic stress by recycling intracellular proteins for nutrient reallocation. Whether the autophagy pathway utilized by breast cancer cells has a survival mechanism or is a feature of cell death is not fully understood. Since the IGF/insulin signaling maintains cellular growth, nutrient utilization, and survival, increased autophagy or autophagic flux might be induced with IGF-I inhibitors as a compensatory survival mechanism. In breast cancer cells treated with anti-IGF1R kinase inhibitors, we observed an increase in autophagic flux; similar to levels induced by nutrient deprivation. Objective: In this study, we examined whether IGF1R inhibitor -induced autophagy is cytoprotective or cytotoxic. If autophagy has a protective role in nutrient-depleted conditions it could reduce the long term efficacy of IGF1R inhibition by making cells refractory to blockade of this signaling system. In this study, we hypothesized that blocking autophagy in combination with anti-IGF1R therapies (antibodies or small molecules) would further enhance growth inhibition in a panel of breast cancer cells types (luminal and basal-like/triple negative). Results: We initially examined whether autophagy inhibitors (chloroquine or bafilomycin A1) had a differential growth effect on breast cancer cells that varied in their sensitivity to IGF1R stimulated growth. We found that low-to-moderate IGF growth dependent MDA-MB-231 and MDA-MB-435A breast cancer cells were more sensitive to chloroquine alone. However, sensitivity to bafilomycin A1 differed between breast cancer cell lines compared to chloroquine. In conditions of cellular stress when autophagy is normally triggered, co-treatment with IGF inhibitor (OSI-906) and chloroquine, increased growth inhibition in all breast cancer cell lines. Further, basal-like breast cancer cells (i.e. low-to-moderate IGF growth dependent cells) had a higher baseline autophagic flux compared to luminal MCF-7L breast cancer cells (i.e. highly IGF-I dependent). Using MCF-7L cells selected for long-term resistance to IGF1R kinase inhibitor (AEW-541), we found that these cells were not sensitivite to chloroquine or Bafilomycin A1 compared to wild type MCF-7Ls. Inhibiting autophagy in combination with anti-IGF therapies could offer benefit over single therapy alone if autophagy inhibitors are given together with IGF1R inhibitors, but not in IGF1R inhibitor resistant cancers. Additionally, targeting autophagy as a single agent therapy may be more beneficial in triple negative breast cancer compared to other subtypes of breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-03.