Hao Lu, Vice President and Executive Director of the Nurix Therapeutics, shared on LinkedIn:
”How does resistance to BTK targeted agents emerge?
Our new paper in Cancer Discovery adds important insights.
In this study, we identified a pre-existing rare but recurrent BTK mutation in patient samples from Phase I clinical trials. Molecular and cellular studies, combined with crystal structures, revealed the molecular mechanism by which it confers pan-resistance to both BTK inhibitors and degraders.
Encouragingly, cells carrying the mutation are at a disadvantage without therapy, and pairing a BTK degrader with venetoclax curbed their expansion, pointing to a potential strategy for addressing this resistance mechanism.
BTK degraders are an exciting and effective new class of therapy for CLL, and understanding resistance mechanisms helps inform new treatment strategies for people living with CLL and other B-cell malignancies.
Read the manuscript:
“Molecular and Structural Basis of Pan-Resistance to BTK Degraders and Inhibitors.”
It was a privilege to work together with the incredibly talented teams at Nurix and our collaborators at Memorial Sloan, the University of Miami and other institutions. Above all, we thank the patients whose participation made this research possible.”
Title: Molecular and Structural Basis of Pan-Resistance to BTK Degraders and Inhibitors
Authors: Quinlan Sievers, Hao Lu, Allison Cool, Stefan Gajewski, Tim Kong, Mark A. Noviski, Sarah Whelan, Yuhan Wang, Lizbeth Mendoza Navarrete, Xiaoli Mi, Emel Ficici, Ratul Mukerji, James N. Iuliano, Jordan Ye, Mateo Sanchez Garcia De Los Rios, Hugo Bousquet, May Tan, Nivetha Brathaban, Nell Narasappa, Ya-Wen Lu, Jennifer Elechko, Maxim I. Maron, Christopher B. Phelps, Jahan Rahman, Ryan Q. Notti, Samantha Sekeres, Erica N. Lamkin, Eduardo Bravo, Alvaro Alencar, Mark D. Ewalt, Prioty Islam, Anthony R. Mato, Lindsey Roeker, Shruti Bhatt, Justin Taylor, Meghan C. Thompson, Gwenn M. Hansen, Omar Abdel-Wahab
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