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

May 28, 2014, University of Chicago Medical Center
A Wright's stained bone marrow aspirate smear from a patient with precursor B-cell acute lymphoblastic leukemia. Credit: VashiDonsk/Wikipedia

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 a correspondence published online May 28 in the New England Journal of Medicine, they show how the mutation triggers resistance. Their finding could guide development of new agents to treat drug-resistant disease.

Ibrutinib received accelerated approval from the Food and Drug Administration for use in in February. It has revolutionized treatment, transforming CLL from a deadly disease to a chronic one. But about eight percent of patients develop resistance to this lifesaving drug.

In this study, the researchers describe a point mutation in one participant enrolled in a multi-center clinical trial. This patient stopped responding to treatment after almost 20 successful months. The mutation destabilized the binding of ibrutinib to its target, a protein that regulates cell replication, allowing to multiply freely.

"In a way, we are repeating, at a faster pace, the story of Gleevec (imatinib), a landmark drug that transformed care for a different type of leukemia," said study senior author Y. Lynn Wang, MD, PhD, professor of pathology at the University of Chicago. "That story began with development of an effective drug with few side effects, but in many patients the leukemia eventually found a way around it after long-term use. So researchers developed second-line drugs to overcome resistance."

The ibrutinib study began in 2010 at Weill Cornell Medical College in New York City, one of several sites for a phase 1 clinical trial of ibrutinib. The researchers recruited 16 patients with CLL whose disease had progressed or relapsed despite multiple treatments.

Wang, who recently moved from Cornell to the University of Chicago, arranged to track the progress of each patient's leukemic cells before and during treatment and to correlate any cellular or molecular changes with each patient's disease activity.

One of the 16 in the trial seemed to be unusual. This 61-year-old woman was diagnosed in 2000 at age 49. She had unsuccessfully received several different treatments before entering the study. Within 18 months after starting ibrutinib, she showed significant improvement. At about 20 months, however, she started to decline, developing a respiratory infection that did not improve with treatment. By 21 months it was clear she was having a relapse. The clinical team increased her dose, with no discernable effect.

Wang's team quickly began analyzing her blood samples, looking for changes that occurred between the period when she was responding well to ibrutinib and after she began to relapse.

Complete gene sequencing and analysis can take a long time so Wang asked a graduate student working on the project, Menu Setty from Christina Leslie's Laboratory at Memorial Sloan Kettering, to focus at first on three proteins, all likely candidates. She gave him the assignment over the July 4, 2012, holiday. On July 5 he had the answer.

He found one tiny but consistent DNA change in about 90 percent of post-relapse cells. It affected one of the three suspected proteins, known as Bruton's tyrosine kinase (BTK). Later on, when they analyzed the entire sets of genes of the patient, they found no other genetic changes that correlated with the patient's clinical course.

BTK made perfect sense as the cause for . It is the primary target of ibrutinib binding and it plays a central role in rapid cell proliferation, as demonstrated in a previous publication by Wang's group and others.

Her team used structural and biochemical measures to confirm that it was this small change in the DNA that made CLL cells resistant to the drug. Biochemical studies indicate that ibrutinib was 500 times less likely to bind to mutant BTK.

In an attempt to save the patient, the team also tested alternative kinase inhibitors against the patient's leukemic cells in the laboratory. They found some kinase inhibitors remained effective against ibrutinib-resistant cells. (These studies are described in a separate manuscript that has been submitted for publication.) Despite the effort, the patient passed away a few weeks later from sepsis.

Although the BTK mutation is one of several mechanisms that underlie resistance to ibrutinib, this study highlights its role in disease development and drug resistance, the authors note. Understanding the molecular and cellular mechanisms of resistance is the first step toward monitoring, early detection and development of novel strategies to overcome drug resistance.

Explore further: Study confirms target of potent chronic leukemia drug

Related Stories

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 ...

Twice-daily pill could turn leukemia into a highly treatable disease

January 23, 2014
(Medical Xpress)—Use of a twice-daily pill could turn a deadly blood cancer into a highly treatable disease, according to scientists at Weill Cornell Medical College who led a multinational research team. Their findings ...

Drug shows surprising efficacy as treatment for chronic leukemia, mantle cell lymphoma

June 19, 2013
Two clinical studies published in the New England Journal of Medicine with an accompanying editorial suggest that the novel agent ibrutinib shows real potential as a safe, effective, targeted treatment for adults with chronic ...

Breakthrough drug on fast-track to help leukemia patients

February 28, 2014
Three very different people gathered recently at University of Colorado Hospital. They were linked by leukemia.

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 ...

Experimental agent may help older people with chronic leukemia

May 16, 2012
The experimental drug ibrutinib (PCI-32765) shows great promise for the treatment of elderly patients with chronic lymphocytic leukemia (CLL), according to interim findings from a clinical trial.

Recommended for you

New approach attacks 'undruggable' cancers from the outside in

January 23, 2018
Cancer researchers have made great strides in developing targeted therapies that treat the specific genetic mutations underlying a patient's cancer. However, many of the most common cancer-causing genes are so central to ...

Study: Cells of three advanced cancers die with drug-like compounds that reverse chemo failure

January 23, 2018
Researchers at Southern Methodist University have discovered three drug-like compounds that successfully reverse chemotherapy failure in three of the most commonly aggressive cancers—ovarian, prostate and breast.

'Hijacker' drives cancer in some patients with high-risk neuroblastoma

January 23, 2018
Researchers have identified mechanisms that drive about 10 percent of high-risk neuroblastoma cases and have used a new approach to show how the cancer genome "hijacks" DNA that regulates other genes. The resulting insights ...

Enzyme inhibitor combined with chemotherapy delays glioblastoma growth

January 23, 2018
In animal experiments, a human-derived glioblastoma significantly regressed when treated with the combination of an experimental enzyme inhibitor and the standard glioblastoma chemotherapy drug, temozolomide.

Researchers identify a protein that keeps metastatic breast cancer cells dormant

January 23, 2018
A study headed by ICREA researcher Roger Gomis at the Institute for Research in Biomedicine (IRB Barcelona) has identified the genes involved in the latent asymptomatic state of breast cancer metastases. The work sheds light ...

Boosting cancer therapy with cross-dressed immune cells

January 22, 2018
Researchers at EPFL have created artificial molecules that can help the immune system to recognize and attack cancer tumors. The study is published in Nature Methods.

0 comments

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.