TAMPA, Fla. and BOSTON - 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. 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 commonly used to treat chronic lymphocytic leukemia and acute myeloid leukemia. 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 respond to the drug eventually develop resistance and tumor recurrence. The team of researchers led by Jianguo Tao, M.D., Ph.D and Jun Qi, Ph.D., 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.
They created model cell lines that were resistant to Venetoclax 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 an 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.
The researchers 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. The study, for the first time, unified genetic alteration and non-genetic adaptive response as a driving force for drug resistance evolution to therapy," said Tao, senior member of the Department of Laboratory Medicine and Hematopathology at Moffitt Cancer Center.
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. 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 in 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," said Qi, assistant professor in medicine at the Department of Cancer Biology Dana-Farber Cancer Institute and Harvard Medical School.
The study was supported in part by grants from the National Cancer Institute (CA179062, CA134807, CA137123, POQ-CA066996-19, P50-CA100707-15, CA211336, P30-CA076292), the Lymphoma Research Foundation, Incyte Corporation, the Leukemia and Lymphoma Society and by the Cortner-Couch Chair for Cancer Research from the University of South Florida School of Medicine.
About Moffitt Cancer Center
Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 50 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt's excellence in research, clinical trials, prevention and cancer control. Moffitt is the No. 6 cancer hospital in the nation and has been listed in U.S. News & World Report as one of the "Best Hospitals" for cancer care since 1999. Moffitt devotes more than 2.5 million square feet to research and patient care. Moffitt's expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest distinction. With more than 6,500 team members, Moffitt has an economic impact in the state of $2.1 billion. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.org, and follow the momentum on Facebook, Twitter and YouTube.
About Dana-Farber Cancer Institute
From achieving the first remissions in childhood cancer with chemotherapy in 1948, to developing the very latest new therapies, Dana-Farber Cancer Institute is one of the world's leading centers of cancer research and treatment. It is the only center ranked in the top 4 of U.S. News and World Report's Best Hospitals for both adult and pediatric cancer care.
Dana-Farber sits at the center of a wide range of collaborative efforts to reduce the burden of cancer through scientific inquiry, clinical care, education, community engagement, and advocacy. Dana-Farber/Brigham and Women's Cancer Center provides the latest in cancer care for adults; Dana-Farber/Boston Children's Cancer and Blood Disorders Center for children. The Dana-Farber/Harvard Cancer Center unites the cancer research efforts of five Harvard academic medical centers and two graduate schools, while Dana-Farber Community Cancer Care provides high quality cancer treatment in communities outside Boston's Longwood Medical Area.
Dana-Farber is dedicated to a unique 50/50 balance between cancer research and care, and much of the Institute's work is dedicated to translating the results of its discovery into new treatments for patients in Boston, and around the world.