Tyrosine kinase gene fusions in cancer: translating mechanisms into targeted therapies

Abstract

Tyrosine kinase fusion genes represent an important class of oncogenes associated with leukaemia and solid tumours. They are produced by translocations and other chromosomal rearrangements of a subset of tyrosine kinase genes, including ABL, PDGFRA, PDGFRB, FGFR1, SYK, RET, JAK2 and ALK. Based on recent findings, this review discusses the common mechanisms of activation of these fusion genes. Enforced oligomerization and inactivation of inhibitory domains are the two key processes that switch on the kinase domain. Activated tyrosine kinase fusions then signal via an array of transduction cascades, which are largely shared. In addition, the fusion partner provides a scaffold for the recruitment of proteins that contribute to signalling, protein stability, cellular localization and oligomerization. The expression level of the fusion protein is another critical parameter. Its transcription is controlled by the partner gene promoter, while translation may be regulated by miRNA. Several mechanisms also prevent the degradation of the oncoprotein by proteasomes and lysosomes, leading to its accumulation in cells. The selective inhibition of the tyrosine kinase activity by adenosine-5'-triphosphate competitors, such as imatinib, is a major therapeutic success. Imatinib induces remission in leukaemia patients that are positive for BCR-ABL or PDGFR fusions. Recently, crizotinib produced promising results in a subtype of lung cancers with ALK fusion. However, resistance was reported in both cases, partially due to mutations. To tackle this problem, additional levels of therapeutic interventions are suggested by the complex mechanisms of fusion tyrosine kinase activation. New approaches include allosteric inhibition and interfering with oligomerization or chaperones.

Fig 1

Structure of the tyrosine kinases involved in TK fusions. Domains that stabilize the inactive conformation are hatched. TM: transmembrane domain (black box); JM: juxtamembrane domain; MYR: myristoylation motif. Breakpoints are indicated by arrows.

Fig 2

Structure and expression of TK hybrid genes and proteins. In wild-type and fusion genes, arrows depict the gene promoter and filled boxes represent exons. The fusion breakpoint is usually located in a large intron, with a few exceptions such as PDGFRA. The partner is in green and the tyrosine kinase in blue. See text for details.

Fig 3

Role of oligomerizatioon in TK fusion activation. OD: oligomerization domain; TK: tyrosine kinase domain. The indicated partner genes harbour an oligomerization domain that was confirmed experimentally.

Fig 4

Overview of the mechanisms of cell transformation by TK fusions. See text for details.