Skye Montoya, discusses research that she was a part of on mechanisms of resistance to noncovalent Bruton’s tyrosine kinase inhibitors in chronic lymphocytic leukemia.
Skye Montoya, a PhD candidate at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, discusses research that she was a part of on mechanisms of resistance to noncovalent Bruton’s tyrosine kinase (BTK) inhibitors in chronic lymphocytic leukemia (CLL).
According to Montoya, resistance to a noncovalent BTK inhibitor was observed in the phase 1/2 BRUIN study (NCT03740529) evaluating pirtobrutinib (Jaypirca) in patients with CLL. What researchers discovered was that resistance arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition.
Based on these data, the development of BTK inhibitors represent a promising option for patients with CLL who have been previously treated with a covalent BTK inhibitor. Findings show new mechanisms of acquired resistance to both noncovalent and covalent BTK inhibitors in CLL, and experts like Montoya continue to characterize the frequency of these genetic events, evaluate resistance mechanisms, and more.
0:10 | The New England paper was discussing resistance that arose from patients that were being treated in the clinical trials with pirtobrutinib, which is the most recent noncovalent BTK inhibitor. These noncovalent BTK inhibitors arose to overcome some of the resistance that was seen to covalent BTK inhibitors. Specifically, the resistance that occurs at the C481S mutation. The use and treatment with noncovalent BTK inhibitors is wonderful for patients as far as a second-line treatment to overcome resistance that might have been seen for covalent BTK inhibitors. But our research focused on why it stopped working for certain patients or how patients acquired mutations that could cause resistance.
0:57 | From that study, we were able to use samples pre-treatment and at the time of resistance or disease progression, and identified different mutations in the catalytic domain of BTK. Then, we used several approaches to definitively show that these mutations were causing the resistance to the drug. The novel and surprising thing was that some of these mutations were actually kinase dead, which is where a lot of the excitement, for me at least, came from, because it asks a very curious question of, why would mutations that prevent inhibition of BTK through BTK inhibitors also the kinase dead? So then it sparked into 2 different projects: Defining the mechanism of how these kinase dead BTK mutations work, and then also coming up with new ways to treat patients that have these BTK mutations. That is a lot of what our newest paper is going to be focused on.