Lymphoma cells may develop resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib using a variety of potentially druggable pathways, opening the door to finding more effective single-agent or combination secondary therapies for patients with the activated B-cell–like diffuse large B-cell lymphoma (ABC DLBCL) subtype who develop resistance to the drug. Data about these pathways to new therapeutic options were presented by Arthur L. Shaffer III, PhD, a staff scientist in the Lymphoid Malignancies Branch of the Center for Cancer Research at the National Cancer Institute. In 2013, ibrutinib was approved for patients with mantle cell lymphoma who have had at least one prior therapy. Early in 2014, the Food and Drug Administration granted ibrutinib accelerated approval to treat patients with chronic lymphocytic leukemia, as well as patients with chronic lymphocytic leukemia who carry a deletion in chromosome 17, based on trial results showing improved overall response rates in patients treated with the drug. Since then, additional data on progression-free survival and overall survival have verified the clinical benefit of the drug in these patients. "Ibrutinib is, at least currently, the blockbuster monotherapy in multiple lymphoid malignancies, including chronic lymphoid leukemia, mantle cell lymphoma, and ABC DLBCL," Dr. Shaffer told ASH Clinical News. "In some patients, it is practically curative, but what we are seeing, because it is in such wide use, are patients whose tumors are resisting this therapy." According to Dr. Shaffer, investigators have a large armamentarium of molecular tools that can be used to elucidate the mechanisms of ibrutinib resistance. Prior research has already shown that ibrutinib resistance may arise due to a mutation of cysteine residues in the active site of BTK â€” to which ibrutinib binds. Dr. Shaffer and colleagues developed multiple, independent ibrutinib-resistant ABC DLBCL cell line models to more fully explore possible mechanisms of ibrutinib resistance. Using these cell lines, Dr. Shaffer and colleagues found one ABC DLBCL model that had mutated BTK in its active site, but not at the cysteine normally mutated in resistant cells; this mutant, in addition to disrupting ibrutinib binding, may be an activating mutation of BTK that promotes lymphoma cell survival. In addition, the investigators found that the majority of ibrutinib-resistant ABC DLBCL models did not mutate BTK, but seemed to up-regulate other potentially druggable survival pathways to circumvent the effects of ibrutinib. "We hope that this research will quickly shorten the practical time between the clinic and the bench, and back into the clinic," Dr. Shaffer said. "We have a host of other drugs that hit other important pathways in lymphomas, and, hopefully, by applying one or more of those as a single agent or in combination with ibrutinib, we will be able to treat resistance as soon as we detect it."
- Shaffer AL. Mechanisms of ibrutinib resistance in the aggressive, ABC-subtype of diffuse large B-cell lymphoma: pathways to new therapeutics options. Presented at: ASH Meeting on Lymphoma Biology; August 10–13; Colorado Springs, CO.