http://ebooksmedicine.net have now been described in a diverse collection of cancers, including a sizable fraction of cholangiocarcinomas, gliomas, acute myeloid leukemias, and sarcomas. Of clinical significance, because the mutated IDH proteins have an altered structure, it has been possible to develop drugs that inhibit mutated IDH and not the normal IDH enzyme. These drugs are now being tested in cancer patients and have produced encouraging therapeutic responses. This developing story is a remarkable example of how detailed understanding of oncogenic mechanisms can yield entirely new kinds of anti-cancer drugs.
Warburg metabolism is a form of pro-growth metabolismfavoring glycolysis over oxidative phosphorylation. It is inducedin normal cells by exposure to growth factors and becomesfixed in cancer cells due to the action of certain drivermutations.
Many oncoproteins (RAS, MYC, mutated growth factor receptors) induce or contribute to Warburg metabolism, and manytumor suppressors (PTEN, NF1, p53) oppose it.
Stress may induce cells to consume their components in aprocess called autophagy. Cancer cells may accumulate mutations to avoid autophagy, or may corrupt the process toprovide nutrients for continued growth and survival.
Some oncoproteins such as mutated IDH act by causing theformation of high levels of “oncometabolites” that alter theepigenome, thereby leading to changes in gene expression thatare oncogenic.
Tumor cells frequently contain mutations in genes that regulate apoptosis, making the cells resistant to cell death. As discussed in Chapter 2, apoptosis, or regulated cell death, refers to an orderly dismantling of cells into component pieces, which are then efficiently consumed by neighboring cells and professional phagocytes without stimulating inflammation. You will recall that there are two pathways that lead to apoptosis: the extrinsic pathway, triggered by the death receptors FAS and FAS-ligand; and the intrinsic pathway (also known as the mitochondrial pathway), initiated by perturbations such as loss of growth factors and DNA damage. Cancer cells are subject to a number of intrinsic stresses that can initiate apoptosis, particularly DNA damage, but also metabolic disturbances stemming from dysregulated growth as well as hypoxia caused by insufficient blood supply. These stresses are enhanced manyfold when tumors are treated with chemotherapy or radiation therapy, which kill tumor cells by activating the intrinsic pathway of apoptosis. Thus, there is strong selective pressure, both before and during therapy, for cancer cells to develop resistance to intrinsic stresses that may induce apoptosis. Accordingly, evasion of apoptosis by cancer cells occurs mainly by way of acquired mutations and changes in gene expression that disable key components of the intrinsic pathway, or that reset the balance of regulatory factors so as to favor cell survival in the face of intrinsic stresses (
Figure 6.25