Metabolic vulnerability in HER2-positive Breast Cancer

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2018

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Abstract

The human epidermal growth factor receptor 2, or HER2, is overexpressed in 20-30% breast cancer patients and is associated with aggressive disease. Therapies targeting HER2, including monoclonal antibodies (trastuzumab and pertuzumab), a small molecule kinase inhibitor (lapatinib) and an antibody-drug conjugate (trastuzumab emtansine), have significantly prolonged the overall survival of HER2-positive breast cancer patients. However, almost all patients develop resistance either from the beginning of therapy or with prolonged treatment in two years.

Previous studies to unveil the resistance mechanisms were mainly focused on acquired resistance, culturing cells with HER2 inhibitors and making comparisons to their parental cells. In order to study the mechanism mediating intrinsic resistance, we conducted a loss-of-function genetic screen using a HER2-amplified cell line that is intrinsically resistant to HER2 inhibitors with the purpose to identify synthetic lethal targets. TALDO1, a gene encoding a metabolic enzyme in the non-oxidative pentose phosphate pathway was identified from the screen. Metabolic profiling with isotope-labeled glucose was used to understand the mechanism. The profiling results indicated that TALDO1 was necessary for cellular NADPH generation to combat increased cellular ROS and support synthesis of lipids as a result of HER2 inhibition.

Importantly, the higher expression of TALDO1 is associated with poor response to HER2-targeted therapy in a small cohort of HER2-positive breast cancer patients, suggesting it could potentially serve as a biomarker to predict patient response.

Together our study explained a novel mechanism mediating intrinsic resistance to HER2 inhibition with significant clinical value. Combined inhibition of HER2 signaling and the pentose phosphate pathway may result in a better clinical outcome.

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Ding, Yi (2018). Metabolic vulnerability in HER2-positive Breast Cancer. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/18235.

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