Identification of Mechanism for Resistance to Ibrutinib in Lymphoma

CR&T Supports Research to Uncover Source of Resistance to Ibrutinib for Lymphoma Patients

Researchers supported by CR&T, including Selena Chen-Kiang Ph.D. and David Chiron, Ph.D. (both of Weill Cornell Medical College), recently discovered the molecular mechanism responsible for causing some mantle cell lymphoma (MCL) patients to be resistant to ibrutinib (imbruvica).

While ibrutinib has shown promise for treating MCL patients, approximately one-third of patients exhibit resistance and others become resistant following an initial positive response. Furthermore, MCL patients commonly struggle with relapse and there are no effective therapeutic options available when tumors begin to grow at a faster rate.

Using genomic and RNA sequencing analysis, Dr. Chen-Kiang and her fellow researchers (including CR&T Medical Advisory Board member, Dr. John Leonard) identified a relapse-specific genetic mutation, C481S in Burton’s Tyrose Kinase (BTK)—the first identified mutation specific to MCL patients who relapse from ibrutinib after a durable response. As a result of their work, it is believed that a combination therapy of palbociclib and ibrutinib or a PI3K inhibitor may offer an effective strategy for overcoming ibrutinib resistance.

CR&T was instrumental in enabling Dr. Chiron to complete his postdoctoral research with Drs. Chen-Kiang and Leonard, paving the way for these important discoveries in the development of genome-based, hypothesis-driven therapies for overcoming drug resistance.