Endocrinol Metab.  2022 Feb;37(1):53-61. 10.3803/EnM.2022.1402.

Development of Metabolic Synthetic Lethality and Its Implications for Thyroid Cancer

• Ju SH
• Lee SE
• Kang YE
• Shong M

• KMID: 2527136
• DOI: http://doi.org/10.3803/EnM.2022.1402

Abstract

Cancer therapies targeting genetic alterations are a topic of great interest in the field of thyroid cancer, which frequently harbors mutations in the RAS, RAF, and RET genes. Unfortunately, U.S. Food and Drug Administration-approved BRAF inhibitors have relatively low therapeutic efficacy against BRAF-mutant thyroid cancer; in addition, the cancer often acquires drug resistance, which prevents effective treatment. Recent advances in genomics and transcriptomics are leading to a more complete picture of the range of mutations, both driver and messenger, present in thyroid cancer. Furthermore, our understanding of cancer suggests that oncogenic mutations drive tumorigenesis and induce rewiring of cancer cell metabolism, which promotes survival of mutated cells. Synthetic lethality (SL) is a method of neutralizing mutated genes that were previously considered untargetable by traditional genotype-targeted treatments. Because these metabolic events are specific to cancer cells, we have the opportunity to develop new therapies that target tumor cells specifically without affecting healthy tissue. Here, we describe developments in metabolism-based cancer therapy, focusing on the concept of metabolic SL in thyroid cancer. Finally, we discuss the essential implications of metabolic reprogramming and its role in the future direction of SL for thyroid cancer.

Keyword

Synthetic lethal mutations; Thyroid neoplasms; Metabolic reprogramming

Figure

• 

  Fig. 1 The principles of synthetic lethality (SL) in cancer. Loss or inhibition of either of the protein products of gene A or B alone, or overexpression of gene A, is viable. However, pharmacological intervention by the partner gene product will result in an SL interaction in tumor cells with a loss-of-function mutation in a tumor suppressor gene (TSG) (A). In addition, pharmacological intervention by the partner gene product will result in a synthetic dosage lethality (SDL) interaction in tumor cells with a gain-of-function mutation or overexpression of the oncogene (B). The yellow star denotes a mutation. The thicker arrow denotes overexpression. The crossed line denotes inhibition of the gene product by pharmacological intervention.

• 

  Fig. 2 Application of metabolic synthetic lethality (SL) to cancer. The main metabolic pathways involved in metabolic reprogramming of cancer cells harboring mutant genes that may provide a target for SL.

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