Resistance to chemotherapy is widespread and usually involves the existence of a small fraction of cancer cells that survive therapy. A number of mechanisms have been proposed to explain the underlying drug-resistant states such as the rewiring of oncogenic signaling pathways or a pre-defined epigenetic state. However, whether metabolic heterogeneity plays a critical role in this process remains poorly studied. Recently, an example of metabolic dependency has been described: drug-resistant cells strongly depend on the anti-ferroptotic protein GPX4 (Hangauer et al. Nature 2017). This raises the possibility that drug resistant cancer cells possess other unique metabolic features that we could exploit for therapy.
Using a panel of different drug-resistant models, we will define the metabolic pathways that therapy-resistant cells become dependent upon. We aim to uncover metabolic liabilities of refractory tumors and target them using in vitro and mouse models to impair cancer recurrence.