추천 논문

Targeting mitochondrial metabolism for precision medicine in cancer

https://www.nature.com/articles/s41418-022-01022-y

Abstract

During decades, the research field of cancer metabolism was based on the Warburg effect, described almost one century ago. Lately, the key role of mitochondria in cancer development has been demonstrated. Many mitochondrial pathways including oxidative phosphorylation, fatty acid, glutamine, and one carbon metabolism are altered in tumors, due to mutations in oncogenes and tumor suppressor genes, as well as in metabolic enzymes. This results in metabolic reprogramming that sustains rapid cell proliferation and can lead to an increase in reactive oxygen species used by cancer cells to maintain pro-tumorigenic signaling pathways while avoiding cellular death. The knowledge acquired on the importance of mitochondrial cancer metabolism is now being translated into clinical practice. Detailed genomic, transcriptomic, and metabolomic analysis of tumors are necessary to develop more precise treatments. The successful use of drugs targeting metabolic mitochondrial enzymes has highlighted the potential for their use in precision medicine and many therapeutic candidates are in clinical trials. However, development of efficient personalized drugs has proved challenging and the combination with other strategies such as chemocytotoxic drugs, immunotherapy, and ketogenic or calorie restriction diets is likely necessary to boost their potential. In this review, we summarize the main mitochondrial features, metabolic pathways, and their alterations in different cancer types. We also present an overview of current inhibitors, highlight enzymes that are attractive targets, and discuss challenges with translation of these approaches into clinical practice. The role of mitochondria in cancer is indisputable and presents several attractive targets for both tailored and personalized cancer therapy.

Facts

Mitochondrial metabolism is reprogrammed in cancer, providing attractive targets for therapy.

Although targeting mitochondrial metabolism proves challenging, several inhibitors of key enzymes are currently in clinical trials.

Combination strategies and novel drugs against metabolic pathways may provide a potential advantage for precision medicine in cancer.

Open questions

Why is it challenging to develop efficient inhibitors for mitochondrial metabolic enzymes?

Which are the mitochondrial enzymes that need more specific and less toxic inhibitors?

Will combination therapies, including immunotherapy/conventional chemotherapeutics/ketogenic or calorie restriction diets together with inhibition of mitochondrial metabolism improve the survival of cancer patients?