The Influence of Metabolism on Drug Response in Cancer

Abstract

Resistance to therapeutic agents, either intrinsic or acquired, is currently a major problem in the treatment of cancers and occurs in virtually every type of anti-cancer therapy. Therefore, understanding how resistance can be prevented, targeted and predicted becomes increasingly important to improve cancer therapy. In the last decade, it has become apparent that alterations in cellular metabolism are a hallmark of cancer cells and that a rewired metabolism is essential for rapid tumor growth and proliferation. Recently, metabolic alterations have been shown to play a role in the sensitivity of cancer cells to widely-used first-line chemotherapeutics. This suggests that metabolic pathways are important mediators of resistance toward anticancer agents. In this review, we highlight the metabolic alterations associated with resistance toward different anticancer agents and discuss how metabolism may be exploited to overcome drug resistance to classical chemotherapy.

Keywords: BRAF inhibitors; bortezomib; breast cancer; cancer metabolism; cisplatin; drug resistance; melanoma; multiple myeloma.

Figure 1

Metabolic pathways associated with cancer. Pathways involved in central carbon metabolism are presented. Metabolic enzymes that are often upregulated in cancer and serve as potential therapeutic targets are shown in purple. These metabolic pathways are involved in the synthesis of building blocks for macromolecules and redox homeostasis, needed for cell proliferation (shown in red boxes). 2PG, 2-phosphoglycerate; 3PG, 3-phoshoglycerate; ATP, adenosine triphosphate; CPT1, carnitine palmitoyltransferase I; F1,6-BP, fructose-1,6-bisphosphate; F2,6-BP, fructose-2,6-bisphosphate; F6P, fructose- 6-phosphate; FASN, fatty acid synthase; FH, fumarase; G6P, glucose-6-phosphate; GCLC, glutamate-cysteine ligase; GLS, glutaminase; Glu, glutamate; GLUT, glucose transporter type; HK2, hexokinase 2; I, complex I; IDH, isocitrate dehydrogenase; II, complex II; III, complex III; IV, complex IV; LDHA, lactate dehydrogenase A; MCT4, monocarboxylate transporter 4; ME, malic enzyme; OAA, oxaloacetate; PDH, pyruvate dehydrogenase complex; PDK1, pyruvate dehydrogenase kinase 1; PEP, phosphoenol pyruvate; PFK1, phosphofructokinase 1; PFK2, phosphofructokinase 2; PGAM1, phosphoglycerate mutase 1; PHGDH, 3-phosphoglycerate dehydrogenase; PKM2, pyruvate kinase M2; PPP, pentose phosphate pathway; R5P, ribose 5-phosphate; SDH, succinate dehydrogenase; SSP, serine synthesis pathway; TCA, tricarboxylic acid cycle; V, complex V.

Figure 2

Metabolic pathways involved in anticancer drug resistance in multiple myeloma (A), lung- and ovarian cancer (B), breast cancer (C), and melanoma (D). Metabolic enzymes that are associated with drug resistance are shown in purple. Metabolic inhibitors that can be used to target drug-resistant cancers are depicted in red. 2-DG, 2-deoxyglucose; 2ME, 2-methoxyestradiol; 6-AN, 6-aminonicotinamide; ATP, adenosine triphosphate; BPTES, bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide; BSO, buthionine sulphoximine; FASN, fatty acid synthase; G6PDH, glucose-6-phosphate dehydrogenase; GCLC, glutamate-cysteine ligase; GLS, glutaminase; HK2, hexokinase 2; I, complex I; II, complex II; III, complex III; IV, complex IV; LDHA, lactate dehydrogenase A; LDHB, lactate dehydrogenase B; mTOR, mammalian target of rapamycin; NQO1, NAD(P)H quinone dehydrogenase; PDH, pyruvate dehydrogenase complex; PDK1, pyruvate dehydrogenase kinase 1; PHGDH, 3-phosphoglycerate dehydrogenase; PPP, pentose phosphate pathway; R5P, ribose 5-phosphate; ROS, reactive oxygen species; SOD2, superoxide dismutase 2; SSP, serine synthesis pathway; TCA, tricarboxylic acid cycle; V, complex V; xCT, glutamate/cysteine xCT antiporter.