Approaching Resistance to Targeted Inhibition of PI3K in Breast Cancer
Annual summary rept. 1 Oct 2008-30 Sep 2011
HARVARD MEDICAL SCHOOL BOSTON MA
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The phosphatidylinositol 3- kinase PI3K-pathway is frequently activated in breast cancer therefore, considerable effort is focused on identifying compounds that can inhibit specific pathway components, in particular the hallmark oncogene PIK3CA. While targeted inhibition of a cancer survival gene holds significant promise, there are concerns that drug resistance may emerge within the cancerous cells, thus limiting clinical efficacy. Using genetically defined human mammary epithelial cells, we evolved resistance to the PI3KmTOR-inhibitor NVP-BEZ235 and by genome-wide copy-number analyses identified MYC and eIF4E amplification within the resistant cells. Importantly, either MYC or eIF4E were required to bypass pharmacological PI3KmTOR inhibition in resistant cells. Furthermore, these cells displayed elevated 5 cap-dependent protein translation. Collectively, these findings suggest that analysis of drivers of protein translation could facilitate the identification of cancer lesions that confer resistance to PI3K-pathway targeted drugs.
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