Metabolic Reprogramming: A Friend or Foe to Cancer Therapy?

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.

Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go?

“…Metabolic reprogramming is a common phenomenon in haematological and solid tumours. In TME, different cell subpopulations reprogram their metabolism to survive, proliferate, metastasize, and develop resistance to cancer therapies [267,268]. Alterations of metabolic pathways include upregulated glycolysis, glutaminolysis, fatty acid catabolism, and low or impaired oxidative phosphorylation [267,269].…”

“…Both ectoproteases and altered metabolism participate in tumour progression. Ongoing pharmacological approaches aim to exploit glycolytic enzymes in cancer therapy [267,268,286]. Thus, ectoproteases may serve as complementary therapeutic targets when aiming to influence metabolic pathways in cancer.…”

Metabolic Reprogramming in Response to Alterations of Mitochondrial DNA and Mitochondrial Dysfunction in Gastric Adenocarcinoma

“…Of note, cancer mitochondria could take over the above task because they are capable of generating ATP and the production of precursors for the biosynthesis of amino acids, lipids, and nucleotides, or controlling cell death [8]. Regarding the classical Warburg effect, mitochondrial metabolic reprogramming was regarded as a new hallmark of cancers [51], because it would offer mitochondrial plasticity to cope with the different environments of different cancers.…”

Role of solute carrier transporters SLC25A17 and SLC27A6 in acquired resistance to enzalutamide in castration‐resistant prostate cancer

“…Accumulating evidence suggests the involvement of metabolic reprogramming in tumor growth, metastasis, and resistance to therapies. 13,23,24 Deregulation of lipogenesis has been shown in the development of tumor recurrence, 25 metastasis, and drug resistance in prostate cancer patients. 26 Enzalutamide (Xtandi ® ), an oral antiandrogen, has demonstrated its benefit in the treatment of advanced-stage and CRPC.…”