Translational Oncology Division, Oncohealth Institute, Fundacion Jimenez Diaz University Hospital, Madrid, Spain.
Adv Exp Med Biol. 2018;1110:23-34. doi: 10.1007/978-3-030-02771-1_3.
Cancer cells rewire their metabolism in order to boost growth, survival, proliferation, and chemoresistance. The common event of this aberrant metabolism is the increased glucose uptake and fermentation of glucose to lactate. This phenomenon is observed even in the presence of O and completely functioning mitochondria. This is known as the "Warburg Effect" and it is a hallmark in cancer. Up to 40% of all CRC's are known to have a mutated (abnormal) KRAS gene, found at differing frequencies in all consensus molecular subtypes (CMS). CMS3 colon cancer molecular subtype contains the so-called 'metabolic tumours' which represents 13% of total CR cases. These tumours display remarkable metabolic deregulation, often showing KRAS mutations (68%). Unfortunately, patients harbouring mutated KRAS are unlikely to benefit from anti-EGFR therapies. Moreover, it remains unclear that patients with KRAS wild-type CRC will definitely respond to such therapies. Although some clinically designed-strategies to modulate KRAS aberrant activation have been designed, all attempts to target KRAS have failed in the clinical assays and KRAS has been assumed to be invulnerable to chemotherapeutic attack. Quest for metabolic inhibitors with anti-tumour activity may constitute a novel and hopeful approach in order to handle KRAS dependent chemoresistance in colon cancer.
癌细胞会重新调整其代谢以促进生长、存活、增殖和化疗耐药性。这种异常代谢的常见事件是葡萄糖摄取增加和葡萄糖发酵为乳酸。即使在有氧气和完全功能的线粒体的情况下，也会观察到这种现象。这被称为“Warburg 效应”，是癌症的一个标志。高达 40%的结直肠癌已知存在突变（异常）的 KRAS 基因，在所有共识分子亚型（CMS）中以不同的频率发现。CMS3 结肠癌分子亚型包含所谓的“代谢肿瘤”，占总 CRC 病例的 13%。这些肿瘤表现出显著的代谢失调，通常显示 KRAS 突变（68%）。不幸的是，携带突变 KRAS 的患者不太可能从抗 EGFR 治疗中获益。此外，目前尚不清楚 KRAS 野生型 CRC 患者肯定会对这些治疗有反应。尽管已经设计了一些调节 KRAS 异常激活的临床设计策略，但针对 KRAS 的所有尝试都在临床检测中失败，并且假设 KRAS 不易受到化疗攻击。寻找具有抗肿瘤活性的代谢抑制剂可能是一种新颖且有希望的方法，以应对结肠癌中依赖 KRAS 的化疗耐药性。
