Metabolic Reprogramming and Drug Resistance

My postdoctoral lab previously showed that the leucine transporter, SLC7A5 mediates nutrient stress adaptation and resistance to endocrine therapy in ER+ breast cancer. Building on this finding, I investigated whether SLC7A5 regulates resistance to CDK4/6i palbociclib, a drug used to treat patients with endocrine therapy-resistant breast cancers. Using multi-omics analyses of 2D cell-line and patient-derived ER+ breast cancer organoid models, I discovered that SLC7A5 is sufficient to promote resistance. 

To understand the mechanisms behind SLC7A5-mediated metabolic reprogramming, I performed steady state metabolomics studies which revealed that while TCA cycle metabolites remain unchanged, SLC7A5 promotes an increase in glycolytic intermediates, suggesting that SLC7A5 may regulate glycolysis to meet energy demands during treatment. Supporting this finding, I found that SLC7A5 overexpression leads to increases in glucose uptake and mRNA expression of the glucose transporter GLUT1. Importantly, my data demonstrate that BCAT2, a critical enzyme involved in leucine breakdown, is required downstream of SLC7A5 to promote higher bioenergetics, GLUT1 expression, and CDK4/6i resistance. Taken together, these data demonstrate that leucine uptake and catabolism are critical for the ability of ER+ breast cancer cells to alter their energy metabolism through glycolysis and become resistant to CDK4/6 inhibition.  My results thus far suggest an unexpected link between leucine catabolism and glycolysis during the development of palbociclib resistance and form the basis for part of my future research program.