Development of Metabolic Synthetic Lethality and Its Implications for Thyroid Cancer

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.

Toward Systems-Level Metabolic Analysis in Endocrine Disorders and Cancer

“…Cancer cells exhibit metabolic reprogramming that supports their heightened energetic and biosynthetic demands. Thyroid cancer represents one of the most common endocrine malignancies, characterized by abnormal growth and proliferation of thyroid follicular cells [38]. Over the past decades, substantial progress has been made in elucidating the metabolic alterations that underlie the development and progression of thyroid cancer [39][40][41].…”

The Role of De novo Serine Biosynthesis from Glucose in Papillary Thyroid Cancer

“…1) Accumu-lating evidence has shown that cellular energy metabolism in remodeled tumors affects tumor behavior, which determines treatment sensitivity. 2,3) Although thyroid cancers harbor genetic mutations that may provide the underlying cause of metabolic heterogeneity 4,5) and altered cellular energy metabolism, the clinical significance of altered cellular energy metabolism remains to be explored.…”