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Although ibrutinib can extend the lives of heavily treated, relapsed, or refractory patients with mantle cell lymphoma (MCL), many become resistant to the drug. A study in September’s Cancer Discovery (2014;4:1022–35) reveals one way that ibrutinib resistance develops and identifies two drugs that may help treat or even prevent it. “It’s a significant advance,” said Nam Dang, M.D. Ph.D., deputy chief of the division of hematology and oncology at the University of Florida College of Medicine in Gainesville. “Ibrutinib is now becoming widely used,” he added. “By knowing a mechanism of resistance, we can come up with rational strategies to circumvent it.” Ibrutinib is the first drug to target and inactivate Bruton tyrosine kinase (BTK), which mediates B-cell receptor signaling to enable B cells to survive and proliferate. In November 2013, the U.S. Food and Drug Administration (FDA) approved ibrutinib to treat MCL on the basis of an “unprecedented” response: 68% of patients went into partial or complete remission and the average duration of response was 13.5 months. But most patients eventually relapse. Selina Chen-Kiang, Ph.D., professor of pathology and laboratory medicine at New York’s Weill Cornell Medical College, and colleagues compared DNA and RNA from normal and tumor cells of patients before, during, and after treatment. BTK genes in tumor cells of patients who developed ibrutinib resistance after responding for at least 14 months had a C481→S mutation. Detectable only at relapse, this mutation hindered ibrutinib from binding to BTK. This mechanism, however, did not explain why about 30% of patients failed to respond to ibrutinib or acquired resistance early. Tumor cells from these patients did not harbor the BTK mutation, suggesting other resistance mechanisms. Further study showed that although ibrutinib did bind to and inactivate BTK, cells expressed high levels of activated PI3K-AKT and cyclindependent kinase 4 (CDK4). (PI3K-AKT proteins promote survival; CDK4 drives MCL cells through the cell cycle.) These two mechanisms appeared to override ibrutinib’s inhibitory action in resistant cells, Chen-Kiang said.

Overcoming Mantle Cell Lymphoma's Ibrutinib Resistance