Credit: Rhoda Baer
Investigators have identified drug combinations that may overcome resistance to ibrutinib in patients with mantle cell lymphoma (MCL).
The group discovered a mutation in Bruton’s tyrosine kinase (BTK) that confers resistance to the drug.
They also found that high levels of PI3K-AKT and CDK4 signaling could explain innate resistance to ibrutinib, so combining a CDK4 inhibitor and a PI3K inhibitor might be effective in patients who don’t respond to ibrutinib.
Selina Chen-Kiang, PhD, of Weill Cornell Medical College in New York, and her colleagues detailed these findings in Cancer Discovery. Some of Dr Chen-Kiang’s colleagues reported relationships with Janssen and Pharmacyclics, the companies developing ibrutinib.
“[Ibrutinib] doesn’t work for about 32% of patients, and their lymphomas are said to have primary resistance to ibrutinib,” Dr Chen-Kiang noted. “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 2 settings.”
Dr Chen-Kiang and her colleagues conducted whole-exome and whole-transcriptome analyses of 5 serial biopsies from a patient with MCL who initially responded to ibrutinib before progressing.
After comparing these data with results from an analysis of healthy tissues from the same patient, the investigators found that a mutation in BTK, the C481S mutation, appeared at relapse.
The researchers found the same mutation at relapse in a second MCL patient 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.
Inhibiting CDK4 with the investigational anticancer drug palbociclib made ibrutinib-resistant lymphoma cells carrying the BTK C481S mutation sensitive to investigational drugs that inhibit PI3K.
And palbociclib made ibrutinib-resistant lymphoma cells harboring normal BTK sensitive to both ibrutinib and investigational drugs that inhibit PI3K. The researchers recently opened a clinical trial to test ibrutinib and palbociclib in combination (NCT02159755).
“We are very excited to have generated data . . . that may be meaningful for patients,” Dr 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 not just important for mantle cell lymphoma but for many forms of cancer.”
