Researchers from Moffitt Cancer Center and Dana-Farber Cancer Institute have discovered a mechanism of drug resistance to Venetoclax (ABT-199) a BCL-2 targeting drug commonly used to treat chronic lymphocyte leukemia and acute myeloid leukemia. The findings, published in the journal Cancer Cell, suggest a possible co-treatment strategy to overcome this resistance.
 
The investigators created model cell lines that were resistant to Venetoclax and compared these cells to the parental cell lines that maintained drug sensitivity. They found that Venetoclax resistance was dependent on both genetic mutations and non-mutational changes. It was also discovered that during treatment with Venetoclax, rare subpopulations of cells lose a genetic amplification of chromosome 18, a trait commonly found in patients with hematologic malignancies, and can survive from drug treatment. This loss contributes to the survival of these cell populations, according to the study.
 
The resistant cells developed non-mutational changes involving transcriptional reprogramming as well. According to the press release, certain regions of DNA called super-enhancers became activated or deactivated in the resistant cells, leading to either a downstream loss or gain in the protein expression, which ultimately contributed to cell survival.
 
“The study, for the first time, unified genetic alteration and non-genetic adaptive response as a driving force for drug resistance evolution to therapy," Jianguo Tao, who led the research team, said in a press release.
 
The transcriptional reprogramming was dependent on a protein called CDK7. These observations suggested that targeting CDK7 may be an effective strategy to prevent Venetoclax resistance, according to the study.
 
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 THZ1 prevented the emergence and maintenance of Venetoclax resistance in models of mantle cell lymphoma and double-hit lymphoma. The patient samples assessment further proved the clinical relevance of this study, which can unveil the drug resistance mechanism in patient care in the future.