Rational drug combinations may overcome ibrutinib resistance

Genomic analyses of tumor and healthy tissue from patients with mantle cell lymphomas provided explanations for two types of resistance to ibrutinib and suggested ways to overcome them in the clinic, according to a new study.

“Ibrutinib, a drug that targets a protein called BTK, shows unprecedented clinical activity against mantle cell lymphoma,” said Selina Chen-Kiang, PhD, professor of pathology and laboratory medicine and professor of microbiology and immunology at Weill Cornell Medical College, New York, New York. “However, the drug doesn't work for about 32% of patients, and their lymphomas are said to have primary resistance to ibrutinib. We are also learning that most patients whose lymphomas respond to ibrutinib eventually relapse because their tumors acquire resistance to the drug.”

In the study, published in Cancer Discovery (2014; doi:10.1158/2159-8290.CD-14-0098), Chen-Kiang and colleagues used whole-exome and whole-transcriptome analysis of five serial biopsies from a patient who had mantle cell lymphoma that initially responded to ibrutinib before progressing to identify reasons why mantle cell lymphomas acquire resistance to ibrutinib. After comparing these data with results from analysis of healthy tissues from the same patient, the researchers found that a mutation in BTK, the C481S mutation, appeared at relapse. The same mutation was detected at relapse in a second patient who had mantle cell lymphoma with acquired resistance to ibrutinib but not in any patients with primary resistance to the drug.

Further analyses revealed 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 anticancer drug palbociclib made ibrutinib-resistant lymphoma cells carrying the BTK C481S 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. The research team has recently opened a clinical trial to test one of these combinations, the selective CDK4/6 inhibitor palbociclib and ibrutinib [NCT02159755].

“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 Chen-Kiang. “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.”

The findings may be relevant for other B cell lymphomas, such as CLL, and a variety of non-Hodgkin lymphomas.

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