この経路は癌細胞にとって生存増殖するのに、大変都合がいい経路で上流のレセプタ－は増殖系のサイトカインであることがほとんど、癌細胞で高発現していることが多いが正常細胞も使用しているために分子標的薬を設計するときは、ほかの組織特異性がある経路酵素の阻害や、高発現経路の阻害を同時にアロステリックに阻害することが重要

例えばHKとNFKBとCYCLINなど

Oncogenic signaling transduction pathways, including the phosphoinositide 3-kinase (PI3K), AKT, and mammalian target of rapamycin (mTOR) pathways, enhance the Warburg effect in tumors, facilitating cancer cell growth and metastasis 

Cancer with activated PI3K/AKT signaling has been revealed to become more aggressive, and AKT pathway activation has been shown as a notable risk factor for earlier recurrence and poor prognosis in liver cancer patients

The PI3K/AKT/mTOR signaling pathway regulates crucial cellular processes in the physiological setting as well as most hallmarks of cancer, including cell cycle, survival, metabolism, motility, and angiogenesis 。 Dysregulation of the phosphatidylinositol 3-kinase (PI3K) is one of the most frequent events in tumorigenesis . Currently, three classes of PI3K are known in the human genome, i.e., class I, class II, and class III .

The Class I PI3K are mainly known to drive tumorigenesis, and the activated Class I PI3K phosphorylates the phosphatidylinositol 4,5- biphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3) . The Class I PI3Ks include four catalytic units encoded by PIK3CA, PIK3CB, PIK3CG, and PIK3CD .

In general, mutation of PI3K catalytic isoform p110α is the most common in human cancers, while the catalytic isoforms p110β, p110δ, and p110γ are rarely mutated but can be overexpressed in cancer .

AKT/mTOR signaling pathway decreases the aerobic glycolysis in HCC cells, thereby eventually abolishing their cell growth . It has been reported that liver cancer is often driven by the activation of AKT/mTOR signaling and that glycolysis activity is increased during HCC growth. Therefore, the suppression of AKT/mTORC1 might be a suitable strategy to prevent HCC development . 

In HCC cell lines, the Warburg effect is elevated with increasing glucose uptake, and it is revealed that miR-873 activates the key glycolytic proteins AKT/mTOR via targeting Nedd4 family-interacting protein 1 (NDFIP1), which initiates metabolic change and causes hepatocellular carcinoma formation and metastasis . Laminin subunit gamma 1 (Lamc 1) decreased the growth of HCC cells by promoting tumor cell death and decreased glucose transportation via the inhibition of expression of pyruvate kinase M2 (PKM2), mechanically reducing the expression of glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA), which implied that the AKT pathway plays a crucial role in the progression of HCC by transforming glucose metabolism .

Furthermore, the mTOR kinase is an essential downstream effector of AKT, and activation of mTOR hampers its downstream effector, eIF4E binding protein (4EBP1). This is stimulating the initiation of protein translation, thereby resulting in increased glucose transporter 1 (GLUT1) translocation and hexokinase 2 (HK2) activity, ultimately enhancing glucose uptake and glycolysis . Cui et al. found that inhibitors of AKT and mTOR repressed the motility of liver cancer cells, decreased glucose consumption and lactate production, and hindered HK2 expression, suggesting that inhibition of the AKT/mTOR signaling axis deterred cell motility by repressing glycolysis in HCC cells .

Moreover, lower AKT activity results in cell cycle arrest and decreased metabolic flux to glycolysis and the tricarboxylic acid (TCA) cycle to repress tumor growth .