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Results of Genomic Analysis Suggest Strategy for Overcoming Ibrutinib Resistance in Mantle Cell Lymphoma

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Key Points

  • The BTK C481S mutation was detected at relapse in mantle cell lymphoma patients with acquired resistance to ibrutinib, but not in any patients with primary resistance to the drug.
  • Blocking CDK4 with the investigational drug palbociclib made ibrutinib-resistant lymphoma cells carrying the BTK C4813 mutation sensitive to investigational drugs that inhibit P13K.
  • In addition, palbociclib made ibrutinib-resistant lymphoma cells harboring normal BTK sensitive to both ibrutinib and investigational drugs that inhibit P13K.

Although the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica) has shown unprecedented clinical activity in mantle cell lymphoma, about 32% of patients do not respond to the drug and majority of responders eventually relapse. Genomic sequencing of tumor and healthy tissue from patients with mantle cell lymphoma with either primary or acquired ibrutinib resistance is providing an explanation for these two types of drug resistance. The findings, published in Cancer Discovery by Chiron et al, not only suggest new approaches for treating mantle cell lymphoma, but also have implications in the treatment of other B-cell lymphomas, such as chronic lymphocytic leukemia.

Study Methodology and Findings

Researchers used longitudinal integrative whole-exome and whole-transcriptome sequencing of five serial biopsies from a patient with mantle cell lymphoma who had initially responded to ibrutinib, but then progressed. After comparing the data with results from analysis of healthy tissues from the same patient, the researchers found that the BTK C481S mutation was present at relapse. The same mutation was detected at relapse in a second patient with mantle cell lymphoma with acquired resistance to ibrutinib, but not in any patients with primary resistance to the drug.

Further analyses showed the consequences of the relapse-specific BTK C481S mutation, including activation of the PI3K and CDK4 signaling pathways, which promote cell survival and proliferation. Blocking CDK4 with the investigational drug palbociclib made ibrutinib-resistant lymphoma cells carrying the BTK C4813 mutation sensitive to investigational drugs that inhibit PI3K. In addition, palbociclib made ibrutinib-resistant lymphoma cells harboring normal BTK sensitive to both ibrutinib and investigational drugs that inhibit PI3K.

“We are very excited to have generated data that we have been able to put together in a way that may be meaningful for patients,” said Selina Chen-Kiang, PhD, Professor of Pathology and Laboratory Medicine and Professor of Microbiology and Immunology at Weill Cornell Medical College in New York, in a statement. “It is also exciting because CDK4 is a new kind of drug target. It controls the cell cycle, which is a central cancer pathway. As such, it is not just important for mantle cell lymphoma, but for many forms of cancer.”

Dr. Chen-Kiang is the corresponding author for the Cancer Discovery article.

The study was funded by the Lymphoma Research Foundation, the Lymphoma Foundation, the Cancer Research and Treatment Fund, the Leukemia & Lymphoma Society, and the National Cancer Institute. Dr. Chen-Kiang declared no conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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