Researchers at UHN's Princess Margaret Cancer Centre have revealed that a protein called topoisomerase 1 (TOP1) – a regulator of DNA organization – can be used as a target for treating cancers involving the MYC protein.
MYC is a regulator of gene expression, which is a process where genes are encoded into proteins. MYC is known to be dysregulated in most human cancers and drive aggressive disease.
"Although the inhibition of MYC can block tumour growth in lab settings, targeting it directly in humans has proven to be a challenge with no small molecule inhibitors of MYC advancing to patient care," says
Dr. Linda Penn, Senior Scientist at the Princess Margaret and senior author of the study.
Peter Lin, a doctoral candidate at the University of Toronto (U of T) and co-first author of the study, adds: “To effectively target MYC and inhibit its function, we decided to employ an alternate strategy and identify specific proteins or processes required for MYC to function as a potent cancer driver."
The researchers used a gene-editing tool called CRISPR to systematically disable the function of different genes in breast cancer cell models where MYC is dysregulated. They then observed which genes were critical for the survival and growth of these tumour cells.
"We identified several genes that encode proteins responsible for proper DNA organization, called R-loop regulators," says Dr. Corey Lourenco, a former postdoctoral researcher in Dr. Penn's lab and co-first author of the study. "We focused on one of these, TOP1, due to the availability of FDA-approved TOP1 inhibitors that are currently used as cancer treatments."
R-loops are DNA structures that can occur during gene expression, playing crucial roles in gene regulation and maintaining genome stability. Regulatory proteins such as TOP1 are important in controlling the initiation or resolution of R-loops, thereby averting potential issues that could lead to DNA damage.
"Upon further investigation, we confirmed that TOP1 was necessary for MYC-driven tumour growth in breast cancer cell models," says Dr. Penn, who is also a professor in the Department of Medical Biophysics at U of T. "One way we did this was by inhibiting TOP1 genetically and through the use of medications.
"We were able to show that inhibiting TOP1 reduced tumour growth in our MYC-driven breast cancer models."
In addition, by examining publicly available datasets, the team found that cancer cells with elevated MYC gene activity were the most vulnerable to TOP1 inhibitors (e.g., topotecan) and this discovery was further validated using patient-derived samples.
Motivated by the prevalent nature of MYC in driving cancer, the researchers propose a model where TOP1 is needed for MYC to drive tumour formation. This suggests that breast cancer cells with high MYC activity rely on TOP1 to resolve R-loop structures and are thereby vulnerable to treatments that block TOP1 and potentially other R-loop regulators.
As several TOP1 inhibitors are clinically available, these findings open new potential therapeutic strategies for these types of cancers.
This work was supported by the Canadian Institutes of Health Research, the U.S. Department of Defense, Instituto de Salud Carlos III, Generalitat de Catalunya, CERCA Program to IDIBELL, and The Princess Margaret Cancer Foundation.
Co-author Dr. David W. Cescon is a consultant, on the advisory board of, and/or reports funding to AstraZeneca, Exact Sciences, Eisai, Gildead, GlaxoSmithKline, Inflex, Inivata, Merck, Novartis, Pfizer, Roche, Saga, Guardant Health and Knight. Dr. Cescon also reports a patent for methods of treating cancers characterized by a high expression level of spindle and kinetochore-associated complex subunit 3 (ska3) gene.
Read more about the study.
