Researchers Discover Why Patients’ Lymphoma May Become Resistant to Specific Therapy

In a study funded in part by the Lymphoma Research Foundation, researchers find the loss of specific protein amplification and transcriptional reprogramming contribute to resistance to venetoclax for patients with B-cell lymphomas

LRF Grantee Jianguo Tao, MD, PhD (H. Moffitt Lee Cancer Center)

Researchers from Moffitt Cancer Center and Dana-Farber Cancer Institute have discovered a mechanism of drug resistance to venetoclax (also known as ABT-199), a BCL-2 targeting drug currently approved for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and acute myeloid leukemia (AML).

Their findings, published in the journal Cancer Cell, also suggest a possible co-treatment strategy to overcome this resistance.

BCL-2 is a protein that promotes cell survival and is highly deregulated in numerous malignancies.  This deregulation can be overcome by treatment with venetoclax.  However, many patients who initially responded to the drug eventually develop resistance and tumor recurrence.

The team of researchers led by LRF Grantee Jianguo Tao, MD, PhD (H. Moffitt Lee Cancer Center) and Jun Qi, PhD (Dana-Farber Cancer Institute), wanted to determine how the BCL-2 inhibitor resistance develops in B-cell lymphomas, such as mantle cell lymphoma (MCL) and aggressive lymphomas with MYC and BCL-2 and/or BCL-6 translocations (sometimes called double-hit lymphoma (DHL)), in order to find strategies to overcome and prevent its occurrence.

They created model cell lines that were resistant to ibrutinib and compared those cells to cell lines that maintained drug sensitivity.  The scientists found that venetoclax resistance was dependent on both genetic mutations and non-mutational changes.

Many blood cancer patients have an amplification of part of chromosome 18.  The researchers discovered that during venetoclax treatment, rare groups of cells lose this genetic amplification and can survive from drug treatment.  Also, this region of chromosome 18 contains the BCL-2 gene, which is the target of venetoclax.

This loss of the target and other cell death regulators in chromosome 18 contribute to the survival of these cell populations, which eventually can develop into drug resistance cells.

The researchers also demonstrated that the resistant cells developed non-mutational changes involving transcriptional reprogramming.

The transcriptional reprogramming was dependent on a protein called CDK7.  These observations suggested that targeting CDK7 may be an effective way to prevent venetoclax resistance.

The researchers conducted a chemical screening of a set of small molecule inhibitors, which further confirmed their hypothesis by showing that combination treatment with venetoclax and the CDK7-targeting inhibitor call THZ1 prevented the emergence and maintenance of venetoclax resistance in MCL and DHL.

Read more about this study in Cancer Cell.

Other authors of this study include LRF Scientific Advisory Board member Eduardo Sotomayor, MD (George Washington University/GW Cancer Center) and LRF Grantee Kai Fu, MD, PhD. Full author listing can be found here.

Researcher Spotlight:
Jianguo Tao, MD, PhD

Dr. Tao is a Professor at the University of South Florida College of Medicine and Senior Member at the H. Lee Moffitt Cancer Center.  A long-time member of the Lymphoma Research Foundation’s Mantle Cell Lymphoma Consortium, Dr. Tao frequently presents his latest research at the Mantle Cell Lymphoma Scientific Workshop; and his presentation on the mechanism of ibrutinib resistance at the 2018 MCL Workshop was covered in the Summer 2018 issue of the Research Report. Read more >