Genomic analyses of tissues from mantle cell lymphoma patients helped researchers explain two types of drug resistance and ways to overcome them in the clinic.
In the study—published in Cancer Discovery, a journal of the American Association for Cancer Research—researchers examined mantle cell lymphoma patients that failed to respond to treatment with ibrutinib (Imbruvica), or initially responded, but then stopped and progressed.
“Ibrutinib, a drug that targets a protein called BTK, shows unprecedented clinical activity against mantle cell lymphoma,” said Selina Chen-Kiang, professor of pathology and laboratory medicine and professor of microbiology and immunology at Weill Cornell Medical College. “However, the drug doesn’t work for about 32 percent 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.”
“The knowledge that we gained from longitudinal RNA and genomic sequencing of mantle cell lymphomas with primary and acquired resistance to ibrutinib allowed us to identify rational drug combinations that may overcome resistance in these two settings,” continued Chen-Kiang. “We recently opened a clinical trial to test one of these combinations, the selective CDK4/6 inhibitor palbociclib and ibrutinib [NCT02159755].”
Researchers 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.
