Scientists at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, and collaborators announced on July 27 that they have identified a rare genetic mutation enabling some blood cancers to evade both approved Bruton tyrosine kinase (BTK) inhibitors and newer BTK degraders. The discovery could influence future treatment strategies for patients with chronic lymphocytic leukemia and related malignancies.
The study, published in Cancer Discovery, describes the BTK A428D mutation as a powerful mechanism conferring resistance to nearly all currently available or developing BTK-targeted therapies. Researchers used molecular, biochemical, and structural analyses to determine that this mutation significantly alters the shape of the BTK protein, preventing drugs from binding effectively.
"Understanding exactly how these resistance mutations emerge gives us a roadmap for identifying patients at risk and developing strategies to stay one step ahead of the disease," said Allison Cool, a researcher at Sylvester and co-first author of the study. Co-author Jayanta Chaudhuri added that "the surprising part was that the BTK A428D has a completely different conformation that makes it impossible for any drugs to bind to it."
The findings indicate that while previous mutations responsible for BTK inhibitor resistance remained susceptible to degraders, A428D resists both approaches. The research also found that although this mutation reduces cancer cell fitness—a potential reason why it is mainly seen in patients treated with degraders—it leaves those who develop it without further options for BTK-targeted therapy. "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.
In preclinical models, combining BTK degraders with another class of drugs targeting BCL2 prevented resistant cancer cells from emerging. Taylor said, "As part of the paper, we showed that adding a different class of drug targeting the BCL2 protein to the BTK degraders can prevent the emergence of resistance." Cool added, "While the A428D mutation explains resistance in some patients, our work is focused on uncovering additional mechanisms...and identifying new therapeutic approaches."
The team continues investigating other causes behind degrader resistance and exploring new strategies aimed at extending benefits from precision medicine therapies.
