Preclinical Study Uncovers Resistance Mechanisms to Lymphoma Therapy and Potential Way to Overcome Them

Preclinical Study Uncovers Resistance Mechanisms to Lymphoma Therapy and Potential Way to Overcome Them

Lymphoma cells can become resistant to therapy as they acquire novel genetic mutations, but a new study has found that they can also become resistant as they reprogram which genes are turned “on” or “off.”

This particular resistance mechanism was seen in B-cell lymphomas in response to treatment with venetoclax (sold as Venclexta and Venclyxto, by AbbVie and Genentech) a chemotherapy used to treat certain types of chronic lymphocytic leukemia, small lymphocytic lymphoma, and acute myeloid leukemia.

The researchers also found that by combining chemotherapy with another agent that blocks the activity of a critical protein for gene reprogramming, they could overcome this type of resistance mechanism, and promote cancer cell death.

These findings were described in the study, “BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models,” that was published in the journal Cancer Cell.

“Emerging evidence suggests that, on drug treatment, small subpopulations of cancer cells evade drug pressure by entering a largely quiescent drug-tolerant ‘persister’ state,” the researchers wrote.

Some of these cells may even grow tolerant to treatment and replicate in the presence of chemotherapy. The survival and growth of these few resistant cells is one of the reasons why some cancer patients who initially respond to a therapy end up seeing their disease return (relapse).

Finding new strategies that prevent the emergence and survival of these cell populations “would have a major impact in the clinic,” the researchers said.

The team, led by Jianguo Tao, MD, PhD, from the Moffitt Cancer Center, and Jun Qi, PhD, from the Dana-Farber Cancer Institutewere interested in looking at how B-cell lymphomas, such as mantle cell lymphoma (MCL) and double-hit lymphoma (DHL) could develop resistance to venetoclax.

Venetoclax belongs to the class of B-cell lymphoma-2 (BCL-2) inhibitors. BCL-2 is a protein that promotes cell survival and is highly unbalanced in numerous cancers, thereby promoting their survival. 

The researchers exposed MCL and DHL cells to venetoclax and selected those cells that were resistant to the treatment. Next, they compared these cells to the original ones that were sensitive to the therapy.

They found that resistance was driven by the occurrence of both new mutations and non-mutational genetic changes.

During venetoclax treatment, rare groups of cells lose part of a genetic sequence on chromosome 18 (18q21) that is commonly found in many patients with blood cancers. This sequence contains additional copies of the BCL-2 gene, which is the target of venetoclax, as well as other genes involved in cell death.

By losing these gene copies, cells were no longer as sensitive to venetoclax and could survive the therapy, eventually growing into resistant cells.

Importantly, the team also found that other, non-mutational changes contribute to resistance, by a mechanism called transcriptional reprogramming.

Cells rely on a transcription process to “read” the information contained in genes and convert it into a blueprint, called messenger RNA (mRNA), which will then be used to produce proteins.

For transcription, and consequently protein production, to happen, genes need to be turned “on,” meaning that they have to be in an active state. This activation involves many gene-specific regulators, including short pieces of DNA called enhancers. Conversely, if enhancers are turned “off,” the genes they control are likely to stop being expressed.

“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,” Tao explained in a press release.

“The study, for the first time, unified genetic alteration and non-genetic adaptive response as a driving force for drug resistance evolution to therapy,” he stated.

After screening for small molecule inhibitors, the team found that this transcriptional reprogramming was dependent on a protein called CDK7 — a potential target to override resistance.

To explore if targeting CDK7 could be a potential strategy to override resistance, the researchers tested a combination of the CDK7 inhibitor THZ1 and venetoclax in their B-cell lymphoma-resistant cells. They saw that this combination was more effective not only at preventing the emergence of resistant cells but also at killing those cells that were already resistant.

A similar anti-cancer activity was seen when they tested the THZ1 and venetoclax combination in lymphoma animal models, as well as in patient samples of MCL, DHL, and diffuse large B cell lymphoma, which further supported the clinical relevance of their findings.

“Disabling CDK7 in combination with ABT-199 [venetoclax] 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,” the researchers wrote.

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