BTK A428D mutation tied to resistance in blood cancer therapies
Sylvester researchers say a rare BTK mutation can block both BTK inhibitors and degraders in CLL and related blood cancers.
By Tom Brennan · Health & Medicine Correspondent
3 min read
Researchers have identified the BTK A428D mutation as a rare genetic change that can help some blood cancers resist major BTK-targeted treatments. The finding matters because it may explain why some patients with chronic lymphocytic leukemia, or CLL, and related B-cell cancers run out of targeted therapy options.
The work was led by scientists at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, with collaborators, and was published in Cancer Discovery. The study, titled “Molecular and Structural Basis of Pan-Resistance to BTK Degraders and Inhibitors,” examined how the mutation affects response to BTK inhibitors and newer BTK degraders.
What is the BTK A428D mutation?
BTK is a protein that many B-cell cancers use for growth and survival. BTK inhibitors are drugs that block that protein, while BTK degraders are designed to remove the protein more directly.
The Sylvester team reported that A428D changes BTK’s shape in a way that keeps drugs from attaching to it. Justin Taylor, a physician-scientist at Sylvester and co-author of the study, said the mutation causes resistance in patients treated with BTK degraders and has also emerged as a resistance mechanism against approved BTK inhibitors.
Taylor said the unexpected part was the altered structure of the mutant BTK protein. “The surprising part was that the BTK A428D has a completely different conformation that makes it impossible for any drugs to bind to it,” he said.
Why does this matter for CLL treatment?
BTK inhibitors have changed care for CLL and other B-cell malignancies, according to the researchers, by targeting a pathway cancer cells rely on. BTK degraders were developed more recently as a way to address resistance that can develop after earlier BTK-directed drugs.
Taylor’s laboratory previously found that the most common BTK inhibitor resistance mutations could still be vulnerable to BTK degraders. The new study found A428D behaves differently, blocking both treatment strategies and creating what the authors describe as broad resistance across BTK-targeted drugs.
“The significance of this finding is that patients who develop these resistance mutations do not have any options for further BTK-targeted therapy,” Taylor said.
The researchers also found that the mutation weakens cancer-cell fitness. They said that trade-off may help explain why A428D has been seen mainly in patients treated with BTK degraders rather than in patients who receive BTK inhibitors alone.
Combination therapy showed a prevention signal
The study also tested a possible way to stop resistance from appearing. In preclinical models, the researchers found that pairing BTK degraders with drugs aimed at the BCL2 protein prevented resistant cancer cells from emerging.
Taylor said the team plans to continue testing combination therapy for CLL. Allison Cool, a Sylvester researcher and co-first author, said the group is also studying other causes of BTK degrader resistance because some patients whose disease progressed did not have the A428D mutation.
The researchers said the findings support using structural biology and genomics to track how cancers change during treatment. They are also exploring new BTK-targeting strategies that could overcome resistance and extend the benefit of precision medicines for patients with blood cancers.
This story draws on original reporting from Medical Xpress.