New Insight into Colorectal Cancer Could Lead to New Therapies

Colon cancer

Approximately 80% of colorectal cancers are linked to mutations in the APC gene. This causes increased levels of the beta-catenin protein, which then accumulates in the cell nucleus. There, it activates a variety of genes that drive cell division and growth.

However, how beta-catenin enters the cell nucleus after the levels rise isn’t well understood. Researchers at the University of Toronto have identified a protein called Importin-11 that transports beta-catenin into the nucleus of colon cancer cells, where it drives cell proliferation. They published their research in the Journal of Cell Biology.

“Because the molecular mechanisms underlying beta-catenin nuclear transport remain unclear, we set out to identify genes required for continuous beta-catenin activity in colorectal cancer cells harboring APC mutations,” said Stephane Angers, professor in the Department of Pharmaceutical Sciences at the University of Toronto’s Leslie Dan Faculty of Pharmacy.

Angers and his research group leveraged CRISPR gene editing technology to develop a new technique to screen the genome for genes that support beta-catenin activity in colorectal cancers cells after its levels have risen from APC mutations. One of the primary genes identified was IPO11. This gene codes a protein called Importin-11, which is involved in nuclear import.

Angers and his colleagues, including graduate student Monika Mis, discovered that Importin-11 binds to beta-catenin and transports it into the nucleus of colorectal cancer cells with APC mutations. By removing Importin-11 from the cells, the researchers prevented beta-catenin from entering the cells’ nucleus and activating the target genes.

“We conclude that Importin-11 is required for the growth of colorectal cancer cells,” Angers said.

They believe that discovering more about how Importin-11 transports beta-catenin into the nucleus could help develop new drugs that block the process and decrease the growth of APC-mutation-based colorectal cancers.

The American Cancer Society estimates that about one in 21 men and one in 23 women in the U.S. will develop colorectal cancer in their lifetimes. Colorectal cancer is also known as bowel cancer, colon cancer, or rectal cancer. It is the second leading cause of death in women and the third leading cause of death for men. The rate has been decreasing due to advanced screening techniques and improved treatments.

The most common treatment for colorectal cancer is surgery, removing the malignant tumors and any nearby lymph nodes.

Earlier this month, Arcus Biosciences and Genentech, a Roche company, announced they were partnering on two clinical trials for colorectal and pancreatic cancer. They will evaluate Arcus’s AB928 in various combination. The first study will evaluate AB928 in third-line metastatic colorectal cancer. It will have two combination arms, the first AB928 and Roche’s Tecentriq (atezolizumab) and Bayer’s Stivarga (regorafenib), and the second, Stivarga and Tecentriq, all compared to Stivarga monotherapy.

And in July, Array BioPharma announced positive results from its Phase III BEACON CRC trial. The trial evaluated a triple combination of Braftovi (encorafenib), a BRAF inhibitor, Mektovia (binimetinib), a MEK inhibitor, and Erbitux (cetuximab), an anti-EGFR inhibitor, in patients with advanced BRAFV600E-mutant metastatic colorectal cancer (mCRC) after one or two lines of therapy. The triple-combination almost doubled overall survival in the patient subpopulation.

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