Study identifies rational drug combinations that may overcome mantle cell lymphoma resistance to ibrutinib

August 8, 2014

Genomic analyses of tumor and healthy tissue from patients with mantle cell lymphomas that fail to respond to treatment with the anticancer drug ibrutinib (Imbruvica) or initially respond but then stop responding and progress, provided explanations for these two types of drug resistance and suggested ways to overcome them in the clinic, according to data published in Cancer Discovery, a journal of the American Association for Cancer Research.

"Ibrutinib, a that targets a protein called BTK, shows unprecedented clinical activity against mantle ," said Selina Chen-Kiang, PhD, professor of pathology and laboratory medicine and professor of microbiology and immunology at Weill Cornell Medical College, New York. "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]."

"Unfortunately, only a subset of mantle cell lymphoma patients respond to ibrutinib and those who do respond eventually relapse," said Lewis C. Cantley, PhD, who directs the Sandra and Edward Meyer Cancer Center at Weill Cornell. "In this paper, the authors conducted a longitudinal study to investigate molecular events that occur during treatment with ibrutinib and identified a mutation in the target of ibrutinib, BTK, that confers resistance to the drug. They also discovered that high levels of PI3K-AKT and CDK4 signaling could explain innate resistance to ibrutinib and showed in ex-vivo studies that a combination of a CDK4 inhibitor and a PI3K inhibitor might be effective for treating patients who do not respond to ibrutinib.

"This study not only suggests new approaches for treating mantle cell lymphoma but also has implications for treatment of other B cell lymphomas, such as CLL, and a diverse group of non-Hodgkin lymphomas," continued Cantley, who is also co-editor-in-chief of Cancer Discovery. Cantley recused himself from the peer review of the study.

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 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.

"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 but for many forms of cancer."

This 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. Chen-Kiang declares no conflicts of interest.

Explore further: Tiny mutation triggers drug resistance for patients with one type of leukemia

Related Stories

Tiny mutation triggers drug resistance for patients with one type of leukemia

May 28, 2014
A multi-institutional team of researchers has pinpointed exactly what goes wrong when chronic lymphocytic leukemia (CLL) patients develop resistance to ibrutinib, a highly effective, precisely targeted anti-cancer drug. In ...

Phase 3 study strengthens support of ibrutinib as second-line therapy for CLL

May 31, 2014
In a head-to-head comparison of two Food and Drug Administration-approved drugs for the treatment of relapsed chronic lymphocytic leukemia (CLL), ibrutinib significantly outperformed ofatumumab as a second-line therapy, according ...

Study confirms target of potent chronic leukemia drug

December 19, 2013
A new study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) helps confirm that a molecule targeted ...

Experimental drug combination selectively destroys lymphoma cells

February 6, 2013
Laboratory experiments conducted by scientists at Virginia Commonwealth University Massey Cancer Center suggest that a novel combination of the drugs ibrutinib and bortezomib could potentially be an effective new therapy ...

Ibrutinib continues strong showing against mantle cell lymphoma

June 19, 2013
In a major international study led by researchers at The University of Texas MD Anderson Cancer Center, the targeted therapy ibrutinib continues to show remarkable promise for the treatment of relapsed or refractory mantle ...

Combination therapy may help patients with follicular lymphoma

June 9, 2014
A new study in The Journal of Experimental Medicine reveals that a high-risk group of patients with follicular lymphoma could benefit from a novel drug combination.

Recommended for you

Outdoor light at night linked with increased breast cancer risk in women

August 17, 2017
Women who live in areas with higher levels of outdoor light at night may be at higher risk for breast cancer than those living in areas with lower levels, according to a large long-term study from Harvard T.H. Chan School ...

Scientists develop novel immunotherapy technology for prostate cancer

August 17, 2017
A study led by scientists at The Wistar Institute describes a novel immunotherapeutic strategy for the treatment of cancer based on the use of synthetic DNA to directly encode protective antibodies against a cancer specific ...

Toxic formaldehyde is produced inside our own cells, scientists discover

August 16, 2017
New research has revealed that some of the toxin formaldehyde in our bodies does not come from our environment - it is a by-product of an essential reaction inside our own cells. This could provide new targets for developing ...

Cell cycle-blocking drugs can shrink tumors by enlisting immune system in attack on cancer

August 16, 2017
In the brief time that drugs known as CDK4/6 inhibitors have been approved for the treatment of metastatic breast cancer, doctors have made a startling observation: in certain patients, the drugs—designed to halt cancer ...

Researchers find 'switch' that turns on immune cells' tumor-killing ability

August 16, 2017
Molecular biologists led by Leonid Pobezinsky and his wife and research collaborator Elena Pobezinskaya at the University of Massachusetts Amherst have published results that for the first time show how a microRNA molecule ...

Popular immunotherapy target turns out to have a surprising buddy

August 16, 2017
The majority of current cancer immunotherapies focus on PD-L1. This well studied protein turns out to be controlled by a partner, CMTM6, a previously unexplored molecule that is now suddenly also a potential therapeutic target. ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.