Researchers have discovered that combining the HDAC inhibitor drug entinostat with the FDA-approved trametinib led to a significant reduction in tumor volume and number of tumors in mice with LKB1-mutated NSCLC. LKB1-mutated tumors are responsible for roughly 20 percent of all NSCLCs, for which there are no effective targeted therapies currently available. The researchers found that HDAC3 plays a critical role in the growth of LKB1-mutant tumors, and targeting it with entinostat can help manage trametinib resistance. This finding may lead to clinical trials to test the new regimen in humans, with potential applications in lymphoma, melanoma, and pancreatic cancer. The study provides a potential therapy for NSCLC patients with the LKB1 genetic mutation.
Combination of Drugs Reduces Lung Tumors in Mice
A new study led by Salk Institute Professor Reuben Shaw and former postdoctoral fellow Lillian Eichner, now an assistant professor at Northwestern University, suggests that a combination of FDA-approved trametinib and entinostat (currently in clinical trials) can be given together to reduce the size and number of tumors in mice with LKB1-mutated NSCLC, a type of non-small cell lung cancer.
Personalizing cancer treatments by finding the right drugs that work for a patient’s specific tumor based on genetic and molecular patterns has been a goal for some time. Targeted therapies have proven highly effective, but they are not available for all cancers, including NSCLCs with a LKB1 genetic mutation.
According to the study published in Science Advances on March 17, 2023, “standard chemotherapy and immunotherapy treatments are not effective” for LKB1-mutated NSCLC cases. However, the combination of trametinib and entinostat produced fewer and smaller tumors in mice with LKB1-mutated NSCLC.
Shaw, senior and co-corresponding author of the study, said, “Our findings demonstrate there is a way to target these cases using drugs that are FDA-approved or already in clinical trials, so this work could easily be used for a clinical trial in humans.”
HDAC Inhibitor Drugs Show Potential in Targeting LKB1-Mutant Tumors
Researchers have discovered that a combination of FDA-approved trametinib and entinostat, an HDAC inhibitor drug currently in clinical trials, can be used to treat non-small cell lung cancer (NSCLC) with the LKB1 genetic mutation. Approximately 20 percent of all NSCLCs have the LKB1 genetic mutation, for which there are no effective targeted therapies currently available.
Histone deacetylases (HDACs) are proteins associated with tumor growth and cancer metastasis, with characteristic overexpression in solid tumors. While several HDAC-inhibitor drugs are already FDA-approved for specific forms of lymphoma, data on their efficacy in solid tumors or whether tumors bearing specific genetic alterations may exhibit heightened therapeutic potential has been lacking. To create a therapy that could target the LKB1 mutation, the researchers turned to HDACs.
The team discovered an unexpectedly critical role for HDAC3 in mouse models of NSCLC. After establishing that HDAC3 was critical for the growth of LKB1-mutant tumors, the researchers examined whether pharmacologically blocking HDAC3 could have a potent effect.
The researchers tested entinostat, an HDAC inhibitor in clinical trials that targets HDAC1 and HDAC3, and trametinib, an FDA-approved inhibitor for a different class of enzymes related to cancer. The team found that a combination of both drugs led to a significant reduction in tumor volume and number of tumors in the lungs of mice with LKB1-mutated NSCLC. Additionally, the team confirmed that entinostat was a viable treatment option in cases where a tumor was resistant to trametinib.
The findings of this study provide a potential therapy for NSCLC patients with the LKB1 genetic mutation. Further clinical trials on humans are needed to confirm the efficacy of the treatment.
HDAC3 a Potential Target for Treating Lung Cancer
Researchers have discovered that HDAC3 plays a critical role in the growth of LKB1-mutant tumors, which are responsible for roughly 20 percent of all non-small cell lung cancers (NSCLCs). HDAC3 is a “druggable vulnerability” that can be targeted to treat NSCLCs with the LKB1 genetic mutation.
The researchers found that combining the HDAC inhibitor drug entinostat with the FDA-approved trametinib led to a significant reduction in tumor volume and number of tumors in mice with LKB1-mutated NSCLC. The team hopes that these findings will lead to clinical trials in humans and transform cancer treatments beyond NSCLC, with potential applications in lymphoma, melanoma, and pancreatic cancer.
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