基于代谢分型的肿瘤生酮治疗敏感性及机制研究进展

Advances in the sensitivity and mechanism of tumor ketogenic therapy based on metabolic typing

能量代谢异常是肿瘤的基本特征之一。尽管靶向肿瘤代谢是一项公认的治疗策略,但临床治疗成功取决于准确的代谢分子分型。近期研究报道了肿瘤生酮治疗相关的两种代谢亚型:糖酵解型和酮体代谢型,两者表现为完全不同的代谢酶谱和线粒体功能状态,以及在体外和体内对生酮干预的不同反应。同时,在p53突变的肿瘤中,糖酵解亚型在葡萄糖限制的状态下可转变为酮体代谢型,随着酮体酶的表达激活及线粒体融合,出现生酮治疗抵抗。通过联用突变p53的变构激活剂,将突变的p53变成野生型的构象,可逆转酮体酶表达激活及线粒体代谢重编,保持稳定的酮体代谢缺陷表型。基于代谢亚型可以选择肿瘤生酮治疗的目标人群,通过基因突变状态可预测生酮治疗敏感性,从而建立精准肿瘤代谢调节治疗策略。

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.