Successful eradication of cancer requires targeted therapy against tumor-initiating cells (TICs). Although these cells are a minority in tumors, TICs are often resistant to chemotherapy, causing cancer to return with a vengeance after treatment.
Now, researchers have found a novel point of weakness in these TICs, opening up new pathways for treatment. In a multi-institutional collaborative effort, scientists under the direction of Wai Leong Tam at A*STAR’s Genomic Institute of Singapore (GIS) discovered that TICs require the amino acid methionine to grow. Conversely, inhibiting the metabolism of methionine in these cells severely crippled their tumor-initiating capabilities.
After performing metabolomic and metabolite tracing analyses, the researchers identified differences in the epigenetic landscape of TICs and the cancer cells they produce. Likened to an on-off switch, epigenetics controls the expression of genes and subsequent production of functional proteins. The amino acid methionine plays a crucial role in epigenetics as its conversion to S-adenosyl-L-homocysteine (SAH) by the enzyme MAT2A regulates gene expression via a process known as histone methylation.
“As the methionine cycle directly influences cellular methylation rates, we naturally thought that this would be a key starting point in characterizing tumorigenic programs in TICs,” explained Tam.
Starving TICs of methionine resulted in a significant reduction of tumor growth after transplantation into mice. Similarly, treating tumor-transplanted mice with the MAT2A inhibitor FIDAS-5 stopped the growth of these tumors. Analysis of human lung adenocarcinoma revealed increased expression of MAT2A levels in the tumors compared to normal lung tissue, demonstrating the clinical relevance of the team’s earlier findings.
“The efficacy of the inhibitor on patient-derived xenografts in vivo was key in demonstrating proof-of-concept that inhibiting methionine cycle activity is a viable therapeutic approach to target TICs in human tumors,” said Zhenxun Wang, a senior postdoctoral fellow, who co-led the study.
“Treatment resistance and cancer relapse, which may be mediated by the presence of TICs, contribute towards the incurability of many cancers,” Wang added. “By targeting the root of tumors, that is, the TICs, we envisage a more durable tumor response and the possibility of overcoming the problems of resistance and relapse.”
Forging ahead, the team is now embarking on a drug discovery effort to develop novel drugs that inhibit methionine cycle activity effectively in human tumors. As different subpopulations of carcinoma cells within a tumor have unique metabolic dependencies, the team is also working on identifying other metabolic genes that can be future targets for cancer therapy.
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore (GIS), the Bioprocessing Technology Institute (BTI) and the Institute of Molecular and Cell Biology (IMCB).