Several non–receptor tyrosine kinases function as signal transduction molecules. In this group, ABL is the best defined with respect to carcinogenesis.
The ABL proto-oncoprotein has tyrosine kinase activity that is dampened by internal negative regulatory domains. As discussed earlier (see
Fig. 6.14 ), in chronic myeloid leukemia and certain acute leukemias, a part of the ABL gene is translocated from its normal abode on chromosome 9 to chromosome 22, where it fuses with part of the breakpoint cluster region (BCR) gene. This fusion gene encodes as BCR-ABL hybrid protein that contains the ABL tyrosine kinase domain and a BCR domain that self-associates, an event that unleashes a constitutive tyrosine kinase activity. Of interest, the BCR-ABL protein activates all of the signals that are downstream of RAS, making it a potent stimulator of cell growth.
The crucial role of BCR-ABL in cancer has been confirmed by the dramatic clinical response of patients with chronic myeloid leukemia to BCR-ABL kinase inhibitors. The prototype of this kind of drug, imatinib mesylate (Gleevec), galvanized interest in design of drugs that target specific molecular lesions found in various cancers (so-called “targeted therapy”). BCR-ABL also is an example of the concept of oncogene addiction, wherein a tumor is profoundly dependent on a single signaling molecule. BCR-ABL fusion gene formation is an early, perhaps initiating, event that drives leukemogenesis. Development of leukemia probably requires other collaborating mutations, but the transformed cell continues to depend on BCR-ABL for signals that mediate growth and survival. BCR-ABL signaling can be seen as the central lodgepole around which the transformed state is “built”. If the lodgepole is removed by inhibition of the BCR-ABL kinase, the structure collapses. In view of this level of dependency, it is not surprising that acquired resistance of tumors to BCR-ABL inhibitors often is due to the outgrowth of a subclone with a mutation in BCR-ABL that prevents binding of the drug to the BCR-ABL protein.
The ultimate consequence of signaling through oncoproteins such as RAS or ABL is inappropriate and continuous stimulation of nuclear transcription factors that drive the expression of growth-promoting genes. Growth autonomy may thus be a consequence of mutations affecting genes that regulate DNA transcription. A host of oncoproteins, including products of the MYC, MYB, JUN, FOS, and REL oncogenes, function as transcription factors that regulate the expression of growth-promoting genes, such as cyclins. Of these, MYC is involved most commonly in human tumors.
Dysregulation of MYC promotes tumorigenesis by simultaneously promoting the progression of cells through the cell cycle and enhancing alterations in metabolism that support cell growth. MYC primarily functions by activating the transcription of other genes. Genes activated by MYC include several growth-promoting genes, including cyclin-dependent kinases (CDKs), whose products drive cells into the cell cycle (discussed next), and genes that control pathways that produce the building blocks (e.g., amino acids, lipids, nucleotides) that are needed for cell growth and division. As mentioned earlier (see
Fig. 6.14 ), dysregulation of MYC results from a (8;14) translocation in Burkitt lymphoma, a highly aggressive B-cell tumor. MYC also is amplified in breast, colon, lung, and many other cancers, while the related NMYC and LMYC genes are amplified in neuroblastomas and small cell cancers of lung, respectively.