Metabolic Reprogramming: A Friend or Foe to Cancer Therapy?

SIMPLE SUMMARY: Tumour cell metabolism is a dynamic and adaptive hallmark of cancer which enables cancer cells to survive, metastasise, proliferate and develop resistance to anti-cancer therapies. Here we review how metabolic reprogramming facilitates cancer cell survival, evasion of cell death processes such as apoptosis and facilitates the development of therapeutic resistance. We discuss how therapeutically-imposed metabolic dependencies can be rationally targeted to revert metabolic reprogramming from a supportive ‘friend’ to a fatal ‘foe’ of cancer cells. ABSTRACT: Drug resistance is a major cause of cancer treatment failure, effectively driven by processes that promote escape from therapy-induced cell death. The mechanisms driving evasion of apoptosis have been widely studied across multiple cancer types, and have facilitated new and exciting therapeutic discoveries with the potential to improve cancer patient care. However, an increasing understanding of the crosstalk between cancer hallmarks has highlighted the complexity of the mechanisms of drug resistance, co-opting pathways outside of the canonical “cell death” machinery to facilitate cell survival in the face of cytotoxic stress. Rewiring of cellular metabolism is vital to drive and support increased proliferative demands in cancer cells, and recent discoveries in the field of cancer metabolism have uncovered a novel role for these programs in facilitating drug resistance. As a key organelle in both metabolic and apoptotic homeostasis, the mitochondria are at the forefront of these mechanisms of resistance, coordinating crosstalk in the event of cellular stress, and promoting cellular survival. Importantly, the appreciation of this role metabolism plays in the cytotoxic response to therapy, and the ability to profile metabolic adaptions in response to treatment, has encouraged new avenues of investigation into the potential of exploiting metabolic addictions to improve therapeutic efficacy and overcome drug resistance in cancer. Here, we review the role cancer metabolism can play in mediating drug resistance, and the exciting opportunities presented by imposed metabolic vulnerabilities.