A new study published this week in the journal Proceedings of the National Academy of Sciences, explains why cancers not only stop responding to kinase inhibitors but come back stronger, a finding that could inform which drugs oncologists use as a first-line treatment.
“When a kinase is switched into the active state, it can lead to processes like cells dividing, a hallmark of cancer,” said Alida Besch, a joint PhD student in the Traaseth group and the Simons Center’s Zhang group, and the study’s first author. “This increased activity is why we hypothesize that cancers come back even stronger, but exactly how gatekeeper mutations increase kinase activity is not well understood.”
Using a multipronged approach, including experiments and computer simulations, the researchers studied FGFR kinases harboring two distinct gatekeeper mutations to determine how the kinase is made more active by the gatekeeper mutations.
Reference
Beach, A., Marsiglia, W.M., Mohammadi, M., Zhang, Y., and Traaseth, N.J., Gatekeeper mutations activate FGF receptor tyrosine kinases by destabilizing the autoinhibited state, Proc. Nat. Acad. Sci. 120 (8) e2213090120 (2023)
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