Drug resistance is a frequently cited issue associated with cancer care, particularly when dealing with targeted agents used in personalized therapy. While genetic abnormalities may be one contributor toward the development of drug resistance, there are a variety of resistance mechanisms that warrant scientific scrutiny.
ABT-199, a BCL-2 homology 3 (BH3) mimetic and selective inhibitor of B-cell chronic lymphocytic leukemia (CLL)/lymphoma 2 (BCL-2), is approved for use in patients with 17p-deleted CLL who have been treated with prior therapy. The therapy has demonstrated in vitro and in vivo activity in non-Hodgkin lymphomas, acute myelogenous leukemia, and multiple myeloma (Clin Adv Hematol Oncol 2014;12(4):224-9).
Resistance to ABT-199 is observed in some patients, yet causative factors associated with this resistance have not been fully explored or elucidated. Research regarding these factors holds pertinent clinical relevance as identification of possible mechanisms of resistance associated with a targeted cancer therapy may aid patient selection and help develop methods to avoid resistance once it starts.
Researchers from Moffitt Cancer Center in collaboration with Dana-Farber Cancer Institute have recently identified a mechanism associated with drug resistance to ABT-199 in patients with B-cell lymphomas, including mantle cell lymphoma (MCL) and double-hit lymphoma (DHL). Their study suggests that inhibition of cyclin-dependent kinase 7 (CDK7) may overcome resistance to ABT-199, at least in B-cell lymphoma models (Cancer Cell 2019;35(5):752-766.e9).
“Our study uncovered a novel mechanism that drives drug resistance against ABT-199, a newly approved drug by the FDA,” study author Jianguo Tao, MD, PhD, hematopathologist and physician-scientist of the Moffitt Cancer Center, told Oncology Times. “It provided a potential biomarker and strategy that could be used to prevent and override resistance in B-cell lymphoma patients treated with ABT-199.”
Study Design & Findings
Both MCL and DHL cell lines resistant to ABT-199 were created and compared with drug-sensitive parental cell lines. Resistance was found to evolve from proliferation of persister clones that lacked 18q21 amplicons harboring BCL2. Simply, some cells lost genetic amplification of the gene and survived during treatment with ABT-199. The region that loses amplification contains the BCL2 gene, the primary target of ABT-199. Surviving cell populations due to the loss of the ABT-199 target as well as additional cell death regulators eventually develop into drug-resistant cells.
In addition to unified genetic mechanisms, the researchers also found non-mutational contributors to ABT-199 resistance. Tao and his colleagues at Moffitt found activation and deactivation of various regions of the DNA in the resistant cells, resulting in either a downstream loss or gain in protein expression. Ultimately, this also caused cell survival and subsequent resistance.
A combination strategy consisting of an inhibitor of CDK7, a protein necessary for transcriptional reprogramming that contributes to ABT-199 resistance, with ABT-199 may be the best approach to combating resistance in select patients, the researchers concluded. Specifically, the study indicates that transcription-targeting agents may represent viable options for disabling drug resistance in the studied lymphomas.
Previous research found alterations pro- and anti-apoptotic family members inherent in resistance mechanisms in cell lines treated with ABT-199 (BMC Cancer 2017;17(1):399). Co-treatment with a MCL-1-selective or BCL-XL-selective inhibitor, in cases where upregulation of anti-apoptotic BCL-2 relatives MCL-1 or BCL-XL were observed, were effective for increasing sensitivity to ABT-199.
Other research, similar to the Moffitt study, suggests that resistance to ABT-199 is mediated by persistent BCL-XL upregulation (Blood 2018;132:1580).
“CDK7 inhibition prevents active enhancer formation at genes, resistance emergence in response to other targeted therapy, and impedes the transcriptional programs required for tumor drug resistance evolution and fatal progression,” explained Tao. “Thus, inhibition of CDK7 may serve as a therapeutic paradigm for enhancing the effectiveness of targeted therapies in lymphomas as well as other solid tumors.”
Despite the risk of resistance to ABT-199, Moffitt researchers are confident in the drug's effectiveness in lymphomas. Tao's sister recently passed away from colon cancer and drug resistance, making his passion and dedication for understanding drug resistance his motivating factor for continuing his research.
“My sister passed away from colon cancer and drug resistance several months ago, and I wish she has had a chance to use this drug,” he said. “It is one of the motivations that keeps me moving for patients like her.”
Moffitt researchers indicate that the disabling of CDK7 with concomitant ABT-199 treatment may support tumor regression in even refractory lymphomas. While these findings may generalize across other hematological malignancies, further research is necessary to determine the potential resistance mechanisms involved in these cancers.
According to Tao, future research with ABT-199 should focus on balancing the drug's efficacy and toxicity profiles.
Researchers at Moffitt are continuing an ongoing investigation into CDK7 inhibition in combination with targeted therapies as a paradigm for enhancing the effectiveness of personalized therapy while preventing the emergence of drug resistance.
Brandon May is a contributing writer.
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