Researchers have discovered what they believe is an explanation for why protein kinase inhibitors lose their effectiveness against cancer and why recurring cancers are more aggressive. As described in a paper to be published Friday in Proceedings of the National Academy of Sciences, it appears that drug resistance develops due to the emergence of genetic mutations in an area of the kinase known as the gatekeeper residue.
Embedded in the kinase, the gatekeeper allows or prevents access to an even-deeper hydrophobic (or water-repelling) pocket. Because kinase inhibitors work by binding to this hydrophobic pocket, mutations to the gatekeeper residue block a drug’s access, reducing its efficacy.
But the team discovered another function of the mutated residue: it de-stabilizes the kinase, paradoxically making it more active. “Even though a drug can no longer bind, the kinase can still function in its destabilized state leading to higher activity which allows for cancer cells to grow and divide,” explained first author Alida Besch, a PhD student in New York University’s Department of Chemistry. “It’s a new idea of how the kinase regains activity so that when cancers return they are more aggressive.”
Kinases need to convert from an inactive to active state to function. Earlier research has suggested that gatekeeper mutations affect the kinase’s active state by strengthening and stabilizing a so-called “hydrophobic spine,” a network of four residues connecting different areas in the kinase.
“But we discovered that it is actually the reverse,” said Besch, of their study on fibroblast growth factor receptors (FGFRs), a family of kinases that frequently mutate in different cancers, including lung and blood cancers. The NYU team focused on two key gatekeeper mutations and studied how the kinases became more active.
“The gatekeeper mutations didn’t stabilize the activity of the kinase,” said Besch. Instead, they destabilized the inactive state of the kinase. “We believe this is because it actually weakens the hydrophobic spine which makes the kinase more active.” The team believes this may at least partially explain why cancer recurrence may be more aggressive.
The NYU researchers suggest these insights will help provide a better idea of what kinase states to target for more effective and lasting cancer therapy. “It may prove useful to not only target the gatekeeper residue but also other sites aside from the hydrophobic pocket,” said Besch, because the pocket is fairly generic across families of kinases. “Adding cocktail treatments might provide a lowered chance of leading to drug resistance,” she says.
“This distinction—that gatekeeper mutations affect the kinase’s inactive state and destabilize it—is important, because we generally want receptor tyrosine kinases to be held in the inactive state. Switching into the active state would usually be dictated by external signals like hormones, not the kinase itself,” explained Yingkai Zhang, professor of chemistry at NYU and the study’s co-senior author. “But if gatekeeper mutations are destabilizing the kinase and shifting it into its active form, this could explain why some cancers come back stronger.”
The team believes these insights will help provide a better idea of what kinase states to target for more effective and lasting cancer therapy. “It may prove useful to not only target the gatekeeper residue but also other sites aside from the hydrophobic pocket,” says Besch, because the pocket is fairly generic across families of kinases. “Adding cocktail treatments might provide a lowered chance of leading to drug resistance,” she says.
