Novel Therapy Holds Promise for Patients With BTK Inhibitor-Resistant CLL

By Patrick Daly - Last Updated: February 21, 2024

Mutations that cause resistance to Bruton’s tyrosine kinase (BTK) inhibitor therapies in patients with chronic lymphocytic leukemia (CLL) fall into two categories, kinase proficient and kinase impaired, according to a report in science.

Notably, the BTK L528W mutation is kinase-impaired and has no BTK activity, conferring resistance to BTK inhibitors; however, CLL with this BTK mutation maintains downstream B cell receptor signaling and B cell survival by promoting binding between BTK protein products (proteoforms) and surrogate kinases, stated the study’s authors, co-led by Skye Montoya, a doctoral candidate; Jessie Bourcier, MD; Mark Noviski, PhD; and Hao Lu, PhD.

Distinct Types of CLL Mutations Confer BTK Inhibitor Treatment Resistance

After identifying this oncogenic scaffold function of BTK, the investigators developed NX-2127, a first-in-class heterobifunctional molecule that induces BTK degradation.

The agent causes the ubiquitin-proteasome system to bind both BTK and cereblon, a receptor of the E3 ubiquitin ligase complex, which leads to polyubiquitination and proteasome-dependent degradation of IKZF1/3 and all recurrent drug-resistant forms of mutant BTK.

In a phase I clinical trial evaluating NX-2127 in patients with CLL, the authors reported the therapy yielded >80% BTK degradation as well as clinical responses in 79% of evaluable patients regardless of BTK mutation category.

“These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients,” the authors concluded.

Reference

Montoya S, Bourcier J, Noviski M, et al. Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science. 2024;383(6682