Stalling the Engine of Resistance: Targeting Cancer Metabolism to Overcome Therapeutic Resistance

Abstract

Cancer cells are markedly different from normal cells with regards to how their metabolic pathways are utilized to fuel cellular growth and survival. Two basic metabolites that exemplify these differences through increased uptake and altered metabolic usage are glucose and glutamine. These molecules can be catabolized to manufacture many of the building blocks required for active cell growth and proliferation. The alterations in the metabolic pathways necessary to sustain this growth have been linked to therapeutic resistance, a trait that is correlated with poor patient outcomes. By targeting the metabolic pathways that import, catabolize, and synthesize essential cellular components, drug resistant cancer cells can often be resensitized to anti-cancer treatments. The specificity and efficacy of agents directed at the unique aspects of cancer metabolism is expected to be high; and may, when in utilized in combination with more traditional therapeutics, present a pathway to surmount resistance within tumors that no longer respond to current forms of treatment.

Overexpression of PCK1 Gene Antagonizes Hepatocellular Carcinoma Through the Activation of Gluconeogenesis and Suppression of Glycolysis Pathways

“…During the past decades, emerging evidence demonstrates that metabolic reprogramming is a typical characteristic of cancers [1]. With the theory becoming a central subject in cancer study, metabolic pathways associated with oncogenesis, tumor progression, and tumor metastasis have been and are being discovered [2].…”

SIRT1/PGC1α-Dependent Increase in Oxidative Phosphorylation Supports Chemotherapy Resistance of Colon Cancer

“…Tumor metabolism has received increased attention over the last decade, mainly in relation to proliferation and specific metabolic alterations. Only recently the metabolic state has been implicated in tumor drug resistance (15,16). Targeting tumor metabolism is now actively being studied as an alternative approach to overcome this problem.…”

“…Drugs that limit the uptake of nutrients or interfere with their use in anabolic pathways have shown efficacy as resistance-modulating agents in several preclinical models (17)(18)(19)(20). However, the link between tumor metabolism and drug resistance is highly complex, it depends on multiple parameters such as oxygen and nutrient availability or the specific drugs that are being used, and the underlying mechanisms still remain to be elucidated (15). In the current study, we used transcriptomics data of liver metastases from chemotherapy-treated and chemo-na€ ve colon cancer patients to identify a novel pathway of drug resistance, involving a change in energy metabolism.…”

Targeting Mitochondrial Oxidative Metabolism in Melanoma Causes Metabolic Compensation through Glucose and Glutamine Utilization

“…For example, the oncogene c-myc reprograms carbon metabolism toward the use of glutamine as a main substrate to maintain ATP levels and promote cell growth (7,8). The fact that tumor cells are highly dependent on specific metabolic and energetic routes could be exploited to develop anticancer therapies (9,10).…”