Currently Viewing:
Newsroom
Currently Reading
Breakthrough Increases Efficacy of B-Cell Lymphoid Malignancy Treatment
December 14, 2019 – Gianna Melillo
Ibrutinib Linked to Increased Hypertension Risk in Study
October 04, 2019 – Mary Caffrey
Pediatric Leukemia Treatment Linked to Increased Risk of Infections, Study Finds
August 16, 2019 – Alison Rodriguez
5 Findings From the August 2019 Issue of AJMC®
August 16, 2019 – Christina Mattina
CMS Says It Will Cover CAR T for Medicare Beneficiaries Nationwide
August 07, 2019 – Allison Inserro
AJMC® in the Press, August 2, 2019
August 02, 2019 – AJMC Staff
This Week in Managed Care: August 2, 2019
August 02, 2019
Blinatumomab Reduces MRD Prior to HCT in Pediatric Patients With B-ALL
July 09, 2019 – Jaime Rosenberg
Undetectable MRD Status in Patients With CLL
July 01, 2019 – Laura Joszt

Breakthrough Increases Efficacy of B-Cell Lymphoid Malignancy Treatment

Gianna Melillo
Ibrutinib, an FDA approved treatment with generally high response rates, can be resisted by some patients. 
Researchers have found a solution to resistance acquired by some users of ibrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor used to treat patients with B-cell lymphoid malignancies.

According to a recent study published in Cell Death & Disease, an increase of the tumor suppressing genes FOXO3a and Phosphatase and tensin homolog (PTEN) in the nucleus of affected cells lowers resistance to BTK inhibition.

“Our data revealed for the first-time increased expression of phosphorylated and cytoplasmic FOXO3a in ibrutinib-resistant (IB-R) cells,” authors said.

BTK is responsible for mediating B-cell receptor signaling. Chronically overreactive BTK can result in B-cell lymphoid malignancies such as chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL). Along with BTK, protein kinase B (AKT) assists in transferring signals within cells and can act as a drug resistant mechanism.

Ibrutinib, an FDA approved treatment with generally high response rates, can be resisted by some patients. According to researchers, up to 5% of patients receiving ibrutinib experience more aggressive activated B-cell (ABC)-DLBCL and up to one-third of these patients develop a relapse of the disease. These numbers prompted researchers to conduct a further investigation into this risk.

Researchers first generated IB-R cells, such as CLL and ABC-DLBCL cells, and exposed them to the drug to better understand the cells’ resistance mechanisms. By conducting a series of different tests, comparing resistant cells with non-resistant cells, researchers observed downregulation of FOXO3a and PTEN levels and a higher activation of AKT in IB-R cells.

When researchers inhibited AKT and restored levels of FOXO3a in IB-R cells they found increased ibrutinib induced apoptosis, or cell death, “demonstrating the importance of these cell survival factors for ibrutinib-resistance.”

In particular, 1 exportin inhibitor, selinexor, worked with the ibrutinib present in IB-R cells to restore FOXO3a and PTEN in affected nuclei, facilitating the intended use of the drug.

“The FOXO3a/PTEN/AKT-axis emerges as a critical determinant of acquired IB-R in CLL and DLBCL. Reduced Nuclear FOXO3a downregulates PTEN…and promotes pro-survival AKT activation in IB-R cells,” researchers said. For future treatments, they recommend a combination of selinexor and ibrutinib as a strategy to sensitize IB-R cells.

Reference

Kapoor I, Li Y, Sharma A, et al. Resistance to BTK inhibition by ibrutinib can be overcome by preventing FOXO3a nuclear export and PI3K/AKT activation in B-cell lymphoid malignancies. Cell Death Dis. 2019;10(12):924. doi: 10.1038/s41419-019-2158-0. 

 
Copyright AJMC 2006-2020 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
x
Welcome the the new and improved AJMC.com, the premier managed market network. Tell us about yourself so that we can serve you better.
Sign Up