Detection and targeting of oncogenic fusions are among the most successful examples of precision cancer medicine. In a recent paper published in the Nature Reviews Clinical Oncology, the investigators from the Department of Medicine and Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA, discuss the biology, detection, clinical importance, and therapeutic implications of oncogenic fusions in solid tumours.
Oncogenic gene fusions are common in patients with solid tumours and occur across a wide spectrum of tumour types. Common methods of fusion detection used in the clinic include break-apart fluorescence in situ hybridization, immunohistochemistry, and next-generation sequencing. Gene fusions frequently involve tyrosine kinases and can cause constitutive kinase activation, augmentation of downstream signalling, and tumour proliferation.
Targeted therapies directed at constitutively activated oncogenic tyrosine kinases have proven remarkably effective against cancers with fusions involving ALK, ROS1, or PDGFB, and the efficacy of this approach continues to be explored in malignancies with RET, NTRK1/2/3, FGFR1/2/3, and BRAF/CRAF fusions. Nevertheless, prolonged treatment with such tyrosine-kinase inhibitors (TKIs) leads to the development of acquired resistance to therapy. This resistance can be mediated by mutations that alter drug binding, or by the activation of bypass pathways.
Second-generation and third-generation TKIs have been developed to overcome resistance, and have variable levels of activity against tumours harbouring individual mutations that confer resistance to first-generation TKIs. The rational sequential administration of different inhibitors is emerging as a new treatment paradigm for patients with tumours that retain continued dependency on the downstream kinase of interest.
Although originally discovered in haematological malignancies, gene fusions are now known to occur in a multitude of different types of cancer. Gene fusions arise as a result of genomic rearrangements, including chromosomal inversions, interstitial deletions, duplications, or translocations, and can drive both the development and progression of cancer. The list of known oncogenic fusions is extensive and continues to grow with the availability of improved detection strategies.
Distribution of kinase fusions across primary tumour sites. Reprinted by permission from Springer Nature.
Large-scale sequencing efforts have identified rare oncogenic fusions across several forms of cancer. Many of these fusions have proven to be viable targets or are the subject of promising ongoing research. In some circumstances, fusions have been demonstrated to confer increased sensitivity to targeted therapy, compared with point mutations in the same gene (such as FGFR2/3).
Owing to the low prevalence of several oncogenic fusions, it is often impractical to clinically test these in typical phase I/II trials that only include patients with tumours of similar histology. Basket trials that involve patients with specific genetic abnormalities, regardless of histology or tumour type, are therefore likely to provide an efficient way to study the clinical significance.
With the continued expansion of clinical sequencing and drug discovery, the treatment of each patient will likely become more individualised based on tumour biology.
Reference
Schram AM, Chang MT, Jonsson P, et al. Fusions in solid tumours: diagnostic strategies, targeted therapy, and acquired resistance. Nature Reviews Clinical Oncology 2017; 14(12):735–748. doi:10.1038/nrclinonc.2017.127