Metabolic Reprogramming in Thyroid Cancer

Abstract

Thyroid cancer is a common endocrine malignancy with increasing incidence globally. Although most cases can be treated effectively, some cases are more aggressive and have a higher risk of mortality. Inhibiting RET and BRAF kinases has emerged as a potential therapeutic strategy for the treatment of thyroid cancer, particularly in cases of advanced or aggressive disease. However, the development of resistance mechanisms may limit the efficacy of these kinase inhibitors. Therefore, developing precise strategies to target thyroid cancer cell metabolism and overcome resistance is a critical area of research for advancing thyroid cancer treatment. In the field of cancer therapeutics, researchers have explored combinatorial strategies involving dual metabolic inhibition and metabolic inhibitors in combination with targeted therapy, chemotherapy, and immunotherapy to overcome the challenge of metabolic plasticity. This review highlights the need for new therapeutic approaches for thyroid cancer and discusses promising metabolic inhibitors targeting thyroid cancer. It also discusses the challenges posed by metabolic plasticity in the development of effective strategies for targeting cancer cell metabolism and explores the potential advantages of combined metabolic targeting.

Keywords: Drug resistance, neoplasm; Immunotherapy; Metabolic networks and pathways; Thyroid neoplasms; Tyrosine kinase inhibitors.

Fig. 1.

Metabolic reprogramming in thyroid cancer and therapeutic resistance. (A) Metabolic reprogramming of thyroid cancer is illustrated. Glucose import is increased by higher levels of glucose transporter 1 (GLUT1) and GLUT3 in the cell membrane. Glycolysis is upregulated by the elevated expression of hexokinase 2 (HK2) and the rate-limiting enzyme of glycolysis, phosphofructokinase-1 (PFK-1). Increased lactate dehydrogenase (LDH) convert pyruvate into lactate, which is exported to the tumor microenvironment via monocarboxylate transporter 4 (MCT4). The final product of glycolysis, pyruvate, is converted into acetyl coenzyme A (acetyl-CoA) in oxygen-enriched conditions, and enters the tricarboxylic acid (TCA) cycle in the mitochondria. Citrate, an intermediate of the TCA cycle, could be exported to the cytoplasm via mitochondrial citrate carrier (CIC) and used for fatty acid synthesis. During glycolysis, the shunt pathways, including the pentose phosphate pathway (PPP) and serine synthesis pathway, are activated to produce ribose-5-phosphate (R5P) and nicotinamide adenine dinucleotide phosphate from PPP and serine and nicotinamide adenine dinucleotide from the serine synthesis pathway. The serine synthesis pathway is closely connected to one-carbon metabolism by the serine hydroxymethyltransferase (SHMT) enzyme. The amino acid transporters, L-type amino acid transporter 1 (LAT1) and alanine-serine-cysteine transporter 2 (ASCT2), are upregulated in thyroid cancer cells. The imported glutamine enters the mitochondria via glutamate carrier 1 (GC1) and is hydrolyzed by glutaminase to yield glutamate, which is converted into α-ketoglutarate (α-KG) to enter the TCA cycle. (B) The pathologic signaling pathways and related metabolic reprogramming in thyroid cancer cells that induce resistance to therapies. G6P, glucose-6-phosphate; G6PD, glucose-6-phosphate dehydrogenase; 6PGD, 6-phosphogluconate dehydrogenase; F6P, fructose-6-phosphate; F1,6BP, fructose 1,6-bisphosphate; 3-PG, 3-phosphoglycerate; THF, tetrahydrofolate; meTHF, 5,10-methylenetetrahydrofolate; EAA, essential amino acids; PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin; MAPK, mitogen-activated protein kinase; HIF-α, hypoxia-inducible factor 1α; ATC, anaplastic thyroid cancer; RAI, radioactive iodine.

Fig. 2.

Metabolic reprogramming induced by genetic alterations and interactions with the tumor microenvironment in thyroid cancer. Thyroid cancer cells manifest distinct metabolic changes, such as elevated glycolysis (the Warburg effect) and alterations in crucial metabolic pathways, contributing to therapeutic resistance and oncogenic progression. These metabolic shifts are influenced by genetic alterations, including the BRAF^V600E mutation, RET/papillary thyroid cancer (PTC) rearrangements, MYC overexpression, and RAS mutations. The tumor microenvironment (TME), comprising diverse cellular components such as cancer-associated fibroblasts (CAFs), extracellular matrix (ECM), endothelial cells, and immune cells, plays a pivotal role in tumor progression and response to therapy. A dynamic metabolic crosstalk within the TME is essential for tumor development. The metabolic reprogramming of immune cells significantly affects their anti-tumor activity. Understanding these complex interactions is crucial for developing targeted cancer therapies. OXPHOS, oxidative phosphorylation; PPP, pentose phosphate pathway; NK, natural killer; TAM, tumor-associated macrophage.