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| Advances in the sensitivity and mechanism of tumor ketogenic therapy based on metabolic typing |
| 1Tang Meng,2 Zhou Fuxiang,1 Cong Minghua,3Shi Hanping |
| 1Comprehensive Oncology Department National Cancer Center/ Cancer Hospital Chinese Academy of Medical Sciences and Peking Union
Medical College Beijing 100021 China
2Department of Radiation and Medical Oncology Hubei Key Laboratory of Tumor Biological
Behaviors/ Hubei Clinical Cancer Study Center Zhongnan Hospital of Wuhan University Wuhan 430071 Hubei China
3Center for
Oncology Nutrition and Metabolism Beijing Shijitan Hospital Capital Medical University / Key Laboratory of Cancer FSMP for State
Market Regulation Beijing 100038 China |
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Abstract Abnormal energy metabolism is one of the fundamental features of cancer. Although targeting cancer metabolism is a
promising therapeutic strategy clinical treatment success depends on accurate molecular and metabolic subtyping. Recent studies have
reported two metabolism-based molecular subtypes associated with cancer ketogenic treatment glycolytic glycolysis
+
/ ketolysis
-
and
ketolytic glycolysis
+
/ ketolysis
+
which were manifested by distinct metabolic enzyme profiles and mitochondrial functional states and
by different responses to ketogenic interventions in vitro and in vivo. Notably in p53-mutated tumors the glycolytic subtype was able
to be converted to the ketolytic subtype upon glucose limitation rendering resistance to ketogenic therapy associated with upregulation
of the ketolytic enzyme and mitochondrial fusion process. However the allosteric activator of mutant p53 can effectively block the
rewired molecular expression and the reprogrammed mitochondrial metabolism by conjugating mutant p53 to a wild-type conformation
thus maintaining a stable ketolytic-deficient phenotype. Based on the metabolic subtypes the target population of cancer ketogenic
therapy can be decided and the sensitivity of ketogenic treatment can be predicted by the mutation status thus establishing a strategy
of precise cancer metabolic modulation therapy.
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Received: 12 June 2023
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