New drug combo targets colorectal cancer mutation

Justin Taylor, M.D., a physician-scientist at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, has found a promising therapeutic strategy for colorectal cancer. Published in Cancer Research, his findings highlight a novel vulnerability in tumour cells with a specific XPO1 gene mutation – and propose a drug combination that may exploit it.

Taylor’s research has earned him a $51,500 Stanley J. Glaser Foundation Research Award, which he will use to advance the project toward clinical application.

“Here we have a new potential combination chemotherapy with science to back up why it might work in patients,” said Taylor, the study’s corresponding author, alongside co-author Dr Hai Dang Nguyen, of the University of Minnesota.

A rare mutation with broad implications

Taylor’s work focuses on XPO1R749Q, a rare mutation in the gene encoding Exportin-1 (XPO1) – a protein that regulates the transport of molecules from the nucleus to the cytoplasm in cells. The mutation has been observed in a small number of colorectal and endometrial cancers.

Using CRISPR-Cas9, Taylor and his team introduced the mutation into colorectal cancer cell lines. They discovered that XPO1R749Q doesn’t accelerate tumour growth, but instead makes tumour cells resistant to irinotecan, a standard chemotherapy drug.

Irinotecan kills cancer cells by inducing DNA damage through its action on Topoisomerase I. But XPO1R749Q ramps up DNA repair mechanisms, notably by boosting levels of replication protein A (RPA). This allows the tumour cells to survive despite DNA damage.

A new combination to overcome resistance

To counteract this resistance, the team turned to selinexor, an FDA-approved drug that inhibits XPO1. When used alone, selinexor killed cancer cells in their model. When combined with irinotecan, the drug duo significantly reduced tumour size in preclinical colorectal cancer models.

Selinexor is already approved for use in advanced multiple myeloma and is under investigation as a maintenance therapy for endometrial cancer.

The combination of selinexor and irinotecan may even be effective in tumours that do not contain XPO1 mutations, due to the fact many tumour types contain elevated levels of XPO1, which may readily be neutralised by selinexor.

From blood cancer discoveries to solid tumour innovation

Taylor’s early focus on XPO1 identified mutations in leukaemia and lymphoma. He brought this research with him to Sylvester in 2020, expanding his investigations into solid tumours like colorectal and endometrial cancers.

Using a dataset of 217,570 cancer patients, Taylor’s team found XPO1R749Q in 96 tumours, predominantly colorectal and endometrial. While rare, the mutation’s impact on treatment resistance makes it a valuable target.

“Dr Taylor’s research opens up a new potential strategy for overcoming resistance in advanced solid tumours, and importantly, in colorectal cancer,” said Jaime Merchán, M.D., co-leader of Sylvester’s Translational and Clinical Oncology Research Program.

Expanding the horizon

Taylor and his collaborators, including first author Dr Tulasigeri M. Totiger, a Sylvester postdoctoral associate, will now test the selinexor-irinotecan combination with immunotherapy agents and explore its potential in endometrial cancer, where XPO1R749Q is also found.

“Exploring such questions further is key to the deep understanding of XPO1’s role in cancer and to developing novel therapeutics,” said Totiger.

The Glaser Award will help fund these next steps, which Taylor hopes will lay the groundwork for a larger grant application to the National Institutes of Health.

“We are focused on translational science and on how we can get our results quickly, to help patients,” Taylor said. “It is exciting for me to apply some of the lessons we learned from studying XPO1 in leukaemia to other cancers.”