Kinase inhibitors follow a well-known pathway in fighting back cancer. But a researcher team at MIT says they've identified a previously "unappreciated" backup mechanism that can be triggered when the inhibitors hit that allows the cancer to progress. And they've identified a combination approach in a preclinical study that may allow for a more durable effect.
When kinase inhibitors shut down the EGFR pathway they also shut down proteases involved in pro-invasion pathways, says the team. Closing those pathways, though, also free up backup systems that are no longer being suppressed by the cancer cells' addiction to the EGFR pathway. As the backup systems come into play, the cancer can roar back into play.
Furthermore, the researchers concluded that they could use the levels of a cleaved protein in the blood to determine who was most at risk of a recurrence, and who would most likely benefit from a combination approach.
"The discovery seems to identify those patients who will go on to receive long-term clinical benefit versus those whose tumors will quickly adapt and circumvent treatment, by virtue of a blood-based test that can be performed at baseline or within days of initiating treatment," says Keith Flaherty, an author of the paper and director of developmental therapeutics at the MGH Cancer Center, who is planning human studies.
The best strategy, says the team, could be a combination of kinase inhibitors with an AXL inhibitor now in the clinic.
"We've discovered a previously unappreciated mechanism involved in resistance to targeted therapeutics," says Douglas Lauffenburger, the Ford Professor of Bioengineering and head of MIT's Department of Biological Engineering. "Its presence appears to be associated with poor response to some kinase inhibitors in clinical patients. And we've demonstrated that in mice adding a drug against this resistance mechanism allows the original targeted drug to work when otherwise it wouldn't."
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