Characterizing Metabolic Alterations in Palbociclib-Resistant ER+ Breast Cancer

Characterizing Metabolic Alterations in Palbociclib-Resistant ER+ Breast Cancer Jessica Shunnarah1, Susan M. Dougherty2, Yoannis Imbert-Fernandez31ULBB Program, 2Department of Medicine, University of Louisville AbstractDiverse mechanisms of resistance to inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6) have been described including cell cycle alterations and metabolic changes. Palbociclib was the first CDK4/6inhibitor approved against estrogen receptor positive (ER+) breast cancer however, the development of resistance has limited its success. This study investigates the changes in the expression of key metabolic enzymes using an in vivo model of palbociclib resistance. Palbociclib-resistant patient derive xenografts (PDXs) were generated by treating NSG mice that had ER+ breast cancer was implanted into the mammary fat pat of NSG mice with palbociclib until the tumors grew in the presence of the drug.. At endpoint, the tumors were harvested, flash frozen, and pulverized for western blot analysis. Our analysis shows the up regulation in some of the metabolic enzymes. We have concluded that resistance to palbociclib ER+ breast cancer increases the expression of Glutaminase (GLS1) in the presence and absence of palbociclib. Palbociclib treatment also leads to an increase 6-phosphofructo-2 kinase/fructose-2,6-biphosphotase-3 (PFKFB3) and Glucose-6-phosphate dehydrogenase (G6PDH) and transketolase in both palbociclib-sensitive and palbociclib-resistant PDX models.Keywords: Palbociclib, estrogen receptor positive, patient derive xenograft, glutaminase, 6-phosphofructo-2 kinase/fructo, glucose-6-phosphate dehydrogenase