Cancer is a disease of altered cell signaling and metabolism, driven by genetic mutations that confer uncontrolled proliferation, resistance to cell death, and metabolic reprogramming. The biochemical changes in cancer cells provide targets for therapy.
Oncogenes and Tumor Suppressors
Oncogenes are mutated or overexpressed versions of normal genes called proto-oncogenes that promote cell growth. Ras is the most frequently mutated oncogene in human cancer, with KRAS mutations found in pancreatic, colorectal, and lung cancers. The mutation impairs GTP hydrolysis, locking Ras in the active GTP-bound state and causing constitutive MAP kinase signaling. MYC is a transcription factor that regulates genes controlling cell growth and metabolism, overexpressed in many cancers through amplification or translocation. PI3K and AKT are frequently activated by mutation or amplification.
Tumor suppressor genes normally restrain cell growth and promote repair or apoptosis. p53 is the most commonly mutated tumor suppressor, inactivated in over half of all cancers. It acts as a transcription factor that responds to DNA damage, oncogenic stress, and hypoxia, inducing cell cycle arrest, DNA repair, or apoptosis. Retinoblastoma protein controls the G1-S cell cycle checkpoint. Loss of Rb function allows unregulated cell cycle entry.
The Warburg Effect
Cancer cells metabolize glucose differently than normal cells, exhibiting aerobic glycolysis. Even in the presence of oxygen, cancer cells convert most glucose to lactate rather than oxidizing it completely. This is called the Warburg effect. While aerobic glycolysis produces less ATP per glucose than oxidative phosphorylation, it is faster and provides biosynthetic precursors needed for cell growth.
The shift to glycolysis is driven by oncogenic signaling. HIF-1, stabilized by hypoxia or oncogene activation, induces expression of glycolytic enzymes, lactate dehydrogenase, and glucose transporters. MYC also promotes glycolytic gene expression. Pyruvate kinase M2, the embryonic isoform expressed in cancer, has low activity that allows accumulation of glycolytic intermediates for biosynthesis. The resulting lactate acidifies the tumor microenvironment, promoting invasion and immune evasion.
Glutamine Metabolism
Many cancers become addicted to glutamine, which supports growth through multiple mechanisms. Glutamine provides nitrogen for nucleotide and amino acid synthesis and carbon for the citric acid cycle through glutaminolysis. Glutamine is converted to glutamate by glutaminase, then to alpha-ketoglutarate, which enters the TCA cycle. This anaplerotic pathway maintains TCA cycle intermediates that are withdrawn for biosynthesis.
MYC directly upregulates glutamine uptake and glutaminase expression. In some cancers, the reverse reaction of IDH generates citrate from glutamine-derived alpha-ketoglutarate in a reductive carboxylation pathway. Mutations in IDH1 and IDH2 produce the oncometabolite 2-hydroxyglutarate, which alters epigenetic regulation and blocks differentiation.
Lipid Metabolism in Cancer
Cancer cells upregulate fatty acid synthesis for membrane production, energy storage, and signaling. ATP-citrate lyase, acetyl-CoA carboxylase, and fatty acid synthase are overexpressed in many cancers. The lipogenic transcription factor SREBP1 is activated by AKT signaling. Exogenous fatty acid uptake also supports tumor growth. Monoacylglycerol lipase liberates free fatty acids for energy and signaling in aggressive cancers.
Tumor Hypoxia and Angiogenesis
Rapid tumor growth creates regions of hypoxia. The hypoxia-inducible factor response allows cells to adapt. HIF-1 induces glucose transporters, glycolytic enzymes, and pyruvate dehydrogenase kinase, which inactivates pyruvate dehydrogenase and suppresses mitochondrial oxidation. HIF also induces vascular endothelial growth factor, promoting angiogenesis that supplies oxygen and nutrients.
Signaling Pathways in Cancer
Several signaling pathways are commonly dysregulated. The PI3K-AKT-mTOR pathway is activated in most cancers through mutation, amplification, or loss of PTEN. mTORC1 promotes protein synthesis and cell growth. The MAP kinase pathway is activated by Ras and B-Raf mutations. The Wnt-beta-catenin pathway is activated in colorectal cancer through APC or beta-catenin mutations. The Notch pathway is activated in T-ALL. Hedgehog signaling is activated in basal cell carcinoma.
Therapeutic Targeting
Molecular insights have enabled targeted therapies. Imatinib inhibits the BCR-ABL kinase in chronic myeloid leukemia. Trastuzumab targets HER2 in breast cancer. Vemurafenib targets mutant BRAF V600E in melanoma. PARP inhibitors exploit synthetic lethality in BRCA-mutant cancers. Metabolic targeting includes drugs inhibiting mutant IDH, glutaminase, and fatty acid synthase. Combination therapies targeting multiple vulnerabilities are increasingly used to overcome resistance and improve outcomes.
