JAK inhibitors promising in colorectal cancer

JAK inhibitors have been found to halt tumor growth in colorectal cancer with a certain genetic mutation, according to a new study. The mutation is found in more than 80% of colorectal cancers.

Multiple JAK inhibitors are currently used, or in clinical trials, for diseases such as rheumatoid arthritis, psoriasis, blood cancers, and myeloproliferative disorders. These drugs target proteins known as JAKs (Janus kinases), and are involved in a signaling pathway that can stimulate tumor growth.

More than 80% of colorectal cancers are driven by a defect in the Wnt signaling pathway, which is parallel to the JAK pathway.

“This genetic defect [in Wnt] triggers a high level of signaling in the pathway, leading to uncontrolled cell growth and therefore cancer,” said Toby Phesse, PhD, of the Walter and Eliza Hall Institute in Melbourne, Australia. “Targeting Wnt signaling directly as a treatment for bowel [colorectal] cancer presents several challenges as normal cells in the intestine rely on low levels of Wnt signaling to renew and keep the gut healthy. Blocking Wnt might prevent tumor growth but it could also cause significant damage to the intestines.”

“Our research showed that blocking JAK proteins could inhibit tumor growth in preclinical models of bowel [colorectal] cancer and human bowel cancer cells that have high levels of Wnt signaling,” said Phesse. “Importantly, we didn't see any side effects in our preclinical models as Wnt signaling could still function in the normal cells of the intestine, as JAK inhibitors only block cell growth in cells with very high Wnt signaling, such as those found in the tumors. This makes it a very attractive therapy for bowel cancer.”

The study, published in Science Signaling (2014; doi:10.1126/scisignal.2005411), found JAK inhibitors were only effective against colorectal cancers that were driven by defective Wnt signaling. Tumors without unusually high levels of Wnt signaling, which is about 10% to 20% of colorectal cancers, did not respond to treatment with JAK inhibitors.

Coauthor Michael Buchert, PhD, also of the Hall Institute, said the results were significant, as several JAK inhibitors have been approved for clinical use for other diseases. “Clinical trials have already shown that JAK inhibitors are safe for human use,” Buchert said. “We hope that this will enable our research to rapidly reach clinical trials for bowel [colorectal] cancer patients and deliver benefits in the near future.”

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