Research reveals why cancer stops responding

More than 70 FDA-approved anticancer drugs are kinase inhibitors, which block kinases (enzymes that add phosphate groups to molecules in cells), chemicals needed for cancer cell signaling and proliferation. inhibits activity. Kinase inhibitors are highly effective, but in the long term some patients experience aggressive relapses that are more difficult to treat and resistant to the original drug.

A new study by New York University researchers published in the journal this week Proceedings of the National Academy of Sciencesexplaining why cancers not only stop responding to kinase inhibitors, but come back stronger.

A major cause of drug resistance, in which cancers become unresponsive to kinase inhibitors, is the emergence of genetic mutations, particularly in regions of the kinase called ‘gatekeeper’ residues. Gatekeepers are deeply embedded in kinases and allow or prevent access to deeper hydrophobic (or water-repellent) pockets.

Since kinase inhibitors function by binding to this hydrophobic pocket, mutations to gatekeeper residues block drug access and reduce their efficacy. But gatekeeper mutations also do something else that could be even more important, according to NYU researchers. It is to activate more kinases.

“The switching of a kinase to its active state can lead to processes such as cell division that are hallmarks of cancer,” said Alida Besh, a Ph.D. student in the Department of Chemistry at New York University and lead author of the study. said. “This increased activity is why we hypothesize that cancers become more robust, but we don’t know exactly how gatekeeper mutations increase kinase activity.”

In their study, the researchers focused on fibroblast growth factor receptors (FGFRs), a family of kinases that are frequently mutated in various cancers, including lung and blood cancers. Treatment of FGFR-associated cancers may include the use of receptor tyrosine kinase inhibitors that bind to the hydrophobic pocket and block the receptor.

Researchers have used multidisciplinary approaches, including experiments (kinase activity assays and nuclear magnetic resonance or NMR spectroscopy) and computer simulations to determine how gatekeeper mutations activate kinases. To do so, we studied FGFR kinases containing two different gatekeeper mutations.

Kinases need to convert from an inactive to an active state to function, and previous studies have shown that gatekeeper mutations influence the active state of kinases by strengthening and stabilizing the so-called ‘hydrophobic spine’. It was suggested to give kinase. However, experiments and simulations reveal a different story. Researchers have found that gatekeeper mutations in the FGFR kinase actually affect the inactive state of the kinase, destabilizing the kinase by weakening the hydrophobic spine, thus allowing the kinase to transition to its active form.

“This distinction is important because gatekeeper mutations affect the inactive state of the kinase, destabilizing it, because we generally want receptor tyrosine kinases to remain inactive. The switch to the active state is typically determined by external signals such as hormones rather than the kinase itself.” Zhang Yingkaiprofessor of chemistry with NYU Simmons Center for Computational Physical Chemistry and co-lead author of the study. “But if gatekeeper mutations destabilize the kinase, turning it into an active form, it may explain why some cancers come back stronger.”

Findings may inform how clinicians choose which first-line cancer treatment to use and whether a combination of drugs instead is more effective in preventing recurrence there is.

“If a treatment targets a kinase that is known to eventually mutate, it may be better to immediately use a cocktail treatment that still binds to the kinase, even if the gatekeeper is mutated. Nate TrasesProfessor of Chemistry at NYU and co-lead author of the study.

Researchers are also looking at how these findings can be used to develop new cancer treatments. One method they are exploring is not only the potential for gatekeeper mutations, but given that these pockets are very similar in about 500 human kinases, it is possible that the hydrophobic to find a place within the kinase other than the sex pocket. It limits the ability of drugs to precisely target specific kinases.

“While that is the goal, there is no single kinase drug on the market that attacks only one type of kinase. It’s one way to do it,” Traaseth said.

Other study authors include William Marsiglia, currently at the University of Alabama at Birmingham, and Moosa Mohammadi, currently at the Oujiang Laboratory in Wenzhou, China. This work was supported by the National Institutes of Health (R01 GM117118, R01 AI108889, R35 GM127040) and the National Science Foundation (1902449).