Targeting 6-Phosphofructo-2-Kinase to increase efficacy of CDK4/6 Inhibitors

This extension request seeks to expand our understanding of CDK4/6 resistance in breast cancer, building upon the groundwork laid by the original grant. The primary focus of this proposal is to understand how altered glutamine metabolism can be exploited as a vulnerability in breast cancer that has developed resistance to CDK4/6 inhibitors. Our central hypothesis is that the aberrant metabolism of glutamine serves to sustain resistance to CDK4/6 inhibition in breast cancer. The main goal is to leverage this identified vulnerability in order to develop targeted therapies capable of eradicating drug-resistant forms of the disease. The specific aims of this extension involve a comprehensive exploration of the role of c-MYC in driving glutamine-induced resistance. This includes investigating c-MYC's role in global metabolic reprogramming, understanding the dependency of increased glutamine metabolism on c-MYC, and examining fuel dependencies following the loss of c-MYC. Additionally, the metabolic fate of glutamine in CDK4/6-resistant cells will be examined. Furthermore, the proposal aims to evaluate the therapeutic efficacy of a novel glutamine antagonist prodrug (JHU083) in patient- derived xenograft (PDX) models of palbociclib-resistant breast cancer. This extension request represents a significant and logical progression from the initial grant, introducing a pioneering evaluation of a novel glutamine antagonist prodrug to target glutamine addiction in ER+ CDK4/6-resistant breast cancer. Anticipating that our studies will yield crucial insights into overcoming drug resistance in breast cancer, we aim to contribute meaningful therapeutic options for a subset of patients currently lacking effective treatment alternatives.