A collaborative study from researchers at the Moffitt Cancer Center and Dana-Farber Cancer Institute has uncovered a mechanism of drug resistance to Venetoclax®, also known as ABT-199, a BCL-2 targeting drug commonly used to treat chronic lymphocytic leukemia and acute myeloid leukemia. BCL-2 is a protein that promotes cell survival and is highly deregulated in numerous malignancies. This deregulation can be overcome by treatment with ABT-199. However, many patients who initially respond to the drug eventually develop resistance and tumor recurrence.

With more targeted therapies being approved each year for cancer, the development of drug resistance to these agents is a growing concern. It has often been assumed that drug resistance is due to the presence or development of additional genetic alterations; however, it is now clear that resistance mechanisms are more complicated. In the current study, the research team wanted to determine how the BCL2 inhibitor resistance develops in B-cell lymphomas, such as mantle cell lymphoma (MCL) and double-hit lymphoma (DHL), in order to find strategies to overcome and prevent its occurrence.

The scientists, who published their findings recently in Cancer Cell through an article titled “BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models,” also suggest a possible co-treatment strategy to overcome this resistance.

Cancer Cell Volume 35, Issue 5, p752-766.e9, May 13, 2019

For their study, the research team created model cell lines that were resistant to ABT-199 and compared these cells to the parental cell lines that maintained drug sensitivity. The scientists found that ABT-199 resistance was dependent on both genetic mutations and non-mutational changes. Many patients with hematologic malignancies have amplification of part of chromosome 18. The researchers discovered that during ABT-199 treatment, rare subpopulations of cells lose this genetic amplification and can survive from drug treatment. Interestingly, this region of chromosome 18 contains the BCL-2 gene, which is the target of ABT-199. This loss of the ABT-199 target and other cell death regulators on chromosome 18 contribute to the survival of these cell populations, which eventually can develop into drug resistance cells.

“Here we report that resistance to the BCL-2 targeting drug ABT-199 in models of mantle cell lymphoma and double-hit lymphoma evolves from an outgrowth of persister clones displaying loss of 18q21 amplicons that harbor BCL2,” the authors wrote. “Further, persister status is generated via adaptive super-enhancer remodeling that reprograms transcription and offers opportunities for overcoming ABT-199 resistance. Notably, pharmacoproteomic and pharmacogenomic screens revealed that persisters are vulnerable to inhibition of the transcriptional machinery and especially to inhibition of cyclin-dependent kinase 7 (CDK7), which is essential for the transcriptional reprogramming that drives and sustains ABT-199 resistance.”

Interestingly, the investigators also demonstrated that the resistant cells developed non-mutational changes involving transcriptional reprogramming.

“Certain regions of the DNA called super-enhancers became activated or deactivated in the resistant cells, leading to either a downstream loss or gain in protein expression, which ultimately contributed to cell survival,” explained senior study investigator Jianguo Tao, PhD, a senior member of the department of laboratory medicine and hematopathology at Moffitt Cancer Center. “The study, for the first time, unified genetic alteration and non-genetic adaptive response as a driving force for drug resistance evolution to therapy.”

The transcriptional reprogramming was dependent on a protein called CDK7. These observations suggested that targeting CDK7 may be an effective strategy to prevent ABT-199 resistance. The researchers conducted a chemical screening of a set of small molecule inhibitors further confirmed this hypothesis by showing that combination treatment with ABT-199 and the CDK7-targeting inhibitor THZ1 prevented the emergence and maintenance of ABT-199 resistance in models of MCL and DHL. The patient samples assessment further proved the clinical relevance of this study, which can unveil the drug resistance mechanism for patient care in the future.

“Disabling CDK7 in combination with ABT-199 is an attractive means to provoke tumor regression of otherwise refractory lymphoma, and such a combination strategy could be applied across a broad spectrum of hematological malignancies,” concluded co-senior study investigator Jun Qi, PhD, assistant professor in medicine at the department of cancer biology at the Dana-Farber Cancer Institute and Harvard Medical School.

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