Gene Fusions Yield Increasingly Broad Spectrum of Targeted Therapies

Jane de Lartigue, PhD
Published: Wednesday, May 03, 2017
We have come a long way since German biologist Theodore Boveri first proposed more than 100 years ago that tumor growth results from chromosomal abnormalities. The identification of chromosomal rearrangements that result in oncogenic gene fusions ushered in the era of molecularly targeted therapies in oncology.

Next-generation sequencing (NGS) technologies have expanded the number of known fusions from several hundred to nearly 10,000 across the spectrum of cancer types, according to recent updates. The highest frequency of gene fusions (90%) is found in hematologic malignancies, particularly lymphomas. Among solid tumors, the highest number of gene fusions have been found in bladder cancer, with thyroid cancer on the opposite end of the spectrum. Although some types of gene fusions are found in only a single tumor type, others are more prolific.

Thus far, only a small portion of known gene fusions have been tested with functional assays in an effort to understand if, and how, they drive cancer. Several dominant types of gene fusion have emerged. Newly identified and well-established gene fusions alike continue to provide promising therapeutic targets and broaden our understanding of cancer development (Table).


Rearranging the Genome

The genomic instability of cancer cells can lead to structural defects in chromosomes as they break apart and join back together in different configurations. This can take different forms: translocations involve whole segments of 1 chromosome transferred to another; inversions occur when a piece of chromosome flips 180 degrees before reinserting; insertions describe the reinsertion of a piece of chromosome back into the same chromosome at a different location; and deletions involve the loss of a portion of a chromosome.

As researchers have been able to examine the genes contained within the breakpoints of rearranged chromosomes, gene fusions emerged as one of the molecular consequences. These occur when 2 previously separate regulatory and/or protein-coding regions from 2 genes are put next to each other in a manner that means they can be “read” by the transcription machinery as a single gene.

Gene fusions can drive cancer in several different ways: through abnormal transcription of otherwise normal cellular genes, resulting in changes in the expression level of that gene; by generating fusion proteins with altered regulation, activity or structure; or via creation of shortened, inactivated tumor suppressor genes.

Most Common Fusion Targets


Among the first chromosomal alterations linked to cancer was the Philadelphia chromosome, a translocation between chromosomes 9 and 22 found in chronic myeloid leukemia (CML) and acute myeloid leukemia. Identification of the BCR-ABL1 fusion gene as the molecular driver behind the Philadelphia chromosome and the tyrosine kinase inhibitors (TKIs) that were developed to target the resulting fusion protein ushered in the era of molecularly targeted therapy in oncology (Figure 1).

This gene fusion results from the reciprocal exchange of genetic material between 2 chromosomes that causes the Abelson kinase (ABL1) gene, which encodes a receptor tyrosine kinase (RTK), to become fused to the breakpoint cluster region (BCR) gene. The ABL1 gene is then “read” as part of the BCR gene, creating a hybrid BCR-ABL protein. Because the BCR protein contains a dimerization domain, it permits activation of the ABL kinase without the need for ligand binding, resulting in a kinase that is always switched on. This general mechanism is thought to be shared by all oncogenic tyrosine kinase fusions identified to date.

Imatinib (Gleevec), a TKI that includes the BCR-ABL protein among its targets, was approved by the FDA for the treatment of CML in 2001. Because the BCR-ABL protein is present in more than 95% of CML cases, imatinib became known as the “magic bullet” that revolutionized the treatment of this cancer.



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Oncology Briefings™: Current Perspectives on Preventing and Managing Tumor Lysis SyndromeJun 30, 20191.0
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