Genomic analyses of tumor and healthy tissue from patients with mantle cell lymphoma (MCLs) that do not respond to treatment with ibrutinib or that stop after an initial response provide clues to the mechanisms of resistance, according to research published Cancer Discovery.
"Ibrutinib, a drug that targets the BTK protein, shows unprecedented clinical activity against mantle cell lymphoma," the study's senior author, Selina Chen-Kiang, PhD, Professor of Pathology and Laboratory Medicine and Microbiology and Immunology at Weill Cornell Medical College, said in a news release. "However, the drug doesn't work for about 32 percent of patients, and their lymphomas 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. We recently opened a clinical trial to test one of these combinations, the selective CDK4/6 inhibitor palbociclib and ibrutinib."
She and her colleagues used whole-exome and whole-transcriptome analysis of five serial biopsies from a patient who had MCL that initially responded to ibrutinib before progressing. 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 MCL 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 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.
"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," Chen-Kiang said. "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 important not just for mantle cell lymphoma but also for many forms of cancer."
The study was supported by funds from the Lymphoma Research Foundation, the Lymphoma Foundation, the Cancer Research and Treatment Fund, the Leukemia and Lymphoma Society, and the National Cancer Institute.