Targeting Glucose Metabolism in HER2 + Breast Cancer

Abstract

The rapid growth and progression of breast tumors is driven by multiple oncogenic mutations. Of these genetic alterations, one of the most important is the increased activity of the human epidermal growth factor receptor 2 (HER2) which is present in a third of breast cancers and associated with aggressive disease and poor survival. Although new agents have improved outcomes in HER2+ breast cancer, many patients continue to progress, develop metastases and die of their disease. Novel and effective targeted therapies are urgently required to improve survival from this devastating cancer. HER2+ cancers consistently exhibit a high reliance on glycolysis to fuel their rapid growth and metastasis. The high glycolytic flux in these tumors is driven by HER2-mediated effectors including the PI3K/AKT and Ras/MAPK pathways and HIF-1α which increase glucose metabolism in part by increasing the activity of a family of enzymes termed the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4). The PFKFBs produce fructose-2,6-bisphosphate (F26BP) which regulates glycolysis by activating a key rate-limiting glycolytic enzyme, 6-phosphofructo-1-kinase (PFK1). In recent studies, we have found that the PFKFB4 family member is highly expressed in a series of HER2+ patient-derived breast tumors relative to normal breast tissue with markedly higher expression in their matched metastatic lymph nodes. We have determined that silencing PFKFB4 markedly reduced F26BP, glycolysis and cell survival in HER2+ breast cancer cells in vitro. We have now developeda novel and potent small molecule PFKFB4 inhibitor that selectively inhibits recombinant PFKFB4 activity, decreases glycolysis and proliferation in HER2+ breast cancer cells and limits their migration and invasion at concentrations that do not affect their viability and suppresses xenograft tumor growth in mice without systemic toxicity. During our studies, we observed that inhibition of a frequently co-expressed PFKFB family member, PFKFB3, increased PFKFB4 expression, indicating that PFKFB4 may compensate for decreased PFKFB3 expression. We now have also found that the simultaneous administration of PFKFB4 and PFKFB3 inhibitors synergistically and significantly decreases proliferation in HER2+ breast cancer cells. These observations carry additional relevance since a novel PFKFB3 inhibitor has recently completed Phase I clinical trial evaluation and compensation by PFKFB4 may limit the efficacy of this and other PFKFB3 inhibitors. Taken together, our current data indicate that targeting PFKFB4 may prove to be a successful treatment option against HER2+ breast tumors and strongly support the further exploration of co-targeting PFKFB4 and PFKFB3 as a potential therapeutic strategy to improve outcomes in this cancer.