Computational tool targets oncofusions’ weakness

When mutations that combine two genes occur, the resulting fusion may act as an oncogene to encode a fusion oncoprotein, which drives tumorigenesis. Although fusion oncoproteins are demonstrated drivers in various cancer types, designing therapies that target them can be complex. Therapeutically targeting fusions has much potential because cancer cells depend on the fusion oncoproteins to thrive. However, the seemingly random manner in which these fusions form and work has hampered drug-development efforts.

To address this knowledge gap, St. Jude computational biologists have developed a tool that comprehensively categorizes and identifies the mechanism underlying the formation of oncogenic fusions in pediatric cancer cells.

“We’ve made something similar to the periodic table for understanding oncogenic fusions,” said Xiaotu Ma, PhD, Department of Computational Biology. “By cataloging the underlying mechanisms, we’ve enabled other scientists to study fusions in better detail.”

In a paper published in Nature Communications, the researchers illustrated that targeting oncogenic fusions with genome-editing tools, such as CRISPR–Cas9, could potentially cure disease. Most oncogenic fusions are currently considered undruggable (with a few exceptions, such as those involving ABL1, ALK, and NTRK). Genome editing presents an exciting curative option for fusions that cannot currently be targeted therapeutically.

The mutations that produce fusion oncoproteins are present only in cancer cells. A precise genetic-editing tool, such as the CRISPR–Cas9 system, could selectively remove the fusion gene from cancer cells, eliminating their ability to produce the hybrid protein needed to thrive, thus leading to a cure.

“The fusion gene–specific sequence only exists in cancer cells; it wouldn’t target any normal cells,” explained first author Yanling Liu, PhD, Department of Computational Biology. “We used CRISPR–Cas9 to perturb the fusion-specific alleles in two cancer cell lines and killed them.”

This work provides proof of principle for a genome-editing cure for cancers; however, it also highlights the difficulties of developing such cures. The cell lines were derived from pediatric cancers with currently poor prognoses, even with treatment. Although genome editing effectively killed one cell line, the other unexpectedly compensated by using multiple splice variants, which are different RNA sequences derived from the same DNA region.

Using CRISPR–Cas9, the scientists disrupted the splice variants of the oncogenic fusion in the second cell line, successfully killing the cancer cells. However, preemptively identifying splice variants is technically challenging, and current genome-editing technologies are not yet efficient enough to bring the approach into a clinical setting for these diseases.

Despite the challenges facing its use in therapy, the computational tool holds exciting potential for identifying the underlying cause of fusion oncoprotein–driven pediatric acute myeloid leukemia. The study serves as proof of principle, offering a new resource in the toolbox of options for developing new interventions for fusion-driven pediatric cancers.