Researchers led by Salk Institute Professor Reuben Shaw and former postdoctoral fellow Lillian Eichner found that a combination of FDA-approved trametinib and entinostat, currently in clinical trials, can effectively reduce the size and number of tumors in mice with LKB1-mutated non-small cell lung cancer (NSCLC). The study suggests that this combination may help manage trametinib resistance, a common problem with current treatments. The researchers discovered that HDAC3 is essential in lung cancer growth and is a druggable vulnerability in therapeutic resistance. The findings may have potential applications in lymphoma, melanoma, and pancreatic cancer. The study is a success story for how basic discovery science can lead to therapeutic solutions.
Combination of Drugs Found to Reduce Lung Tumors with LKB1 Genetic Mutation
According to a study led by Salk Institute Professor Reuben Shaw and former postdoctoral fellow Lillian Eichner, a combination of FDA-approved trametinib and entinostat, currently in clinical trials, can reduce the size and number of tumors in mice with LKB1-mutated non-small cell lung cancer (NSCLC). The findings were published in Science Advances on March 17, 2023.
Around 20% of all NSCLCs have the LKB1 genetic mutation, making it challenging to find targeted therapies. The researchers focused on histone deacetylases (HDACs), which are proteins linked to tumor growth and metastasis. They conducted a genetic analysis of HDAC3 in mouse models of NSCLC, revealing a crucial role for HDAC3 in the growth of LKB1-mutant tumors.
Pharmacologically blocking HDAC3 with HDAC-inhibitor drugs, such as entinostat, had a potent effect, reducing tumor size and number. Combining entinostat with trametinib produced even better results. The combination of drugs could target non-small cell lung cancer cases with the LKB1 mutation that are currently resistant to chemotherapy and immunotherapy treatments.
The study highlights the need for personalized cancer treatments that use specific genetic and molecular patterns to find effective therapies. Finding the right drugs for a patient’s specific tumor can be challenging, but targeted therapies can be highly effective. By using a combination of drugs that are already FDA-approved or in clinical trials, this study offers a promising path forward for developing a therapy for patients with LKB1-mutated NSCLC.
This research demonstrates the potential for combining drugs to produce better outcomes for patients with challenging-to-treat cancers. By identifying the specific genetic mutations associated with tumors, researchers can develop personalized treatments that are more effective and cause fewer side effects. The study provides a starting point for further research and clinical trials that could lead to improved cancer treatments in the future.
Entinostat and Trametinib Combination Proven Effective in Reducing Lung Tumor Growth
Researchers led by Salk Institute Professor Reuben Shaw and former postdoctoral fellow Lillian Eichner have found that a combination of FDA-approved trametinib and entinostat, currently in clinical trials, can effectively reduce the size and number of tumors in mice with LKB1-mutated non-small cell lung cancer (NSCLC). The findings, published in Science Advances on March 17, 2023, suggest that this combination may help manage trametinib resistance, a common problem with current treatments.
Entinostat is an HDAC inhibitor in clinical trials that targets HDAC1 and HDAC3. Trametinib is an inhibitor for a different class of enzymes related to cancer. The researchers believed that a drug that targets HDAC3, such as entinostat, could help manage trametinib resistance because that protein relies on HDAC3. After treating mice with LKB1-mutated lung cancer with variable treatment regimens for 42 days, the team found that mice given both entinostat and trametinib had 79% less tumor volume and 63% fewer tumors in their lungs than the untreated mice.
The researchers confirmed that entinostat is a viable treatment option in cases where a tumor is resistant to trametinib. The findings may lead to clinical trials to test the new regimen in humans, since entinostat is already in clinical trials and trametinib is FDA-approved. The study highlights the potential for combining drugs to produce better outcomes for patients with challenging-to-treat cancers.
The researchers discovered that HDAC3 is essential in lung cancer growth and is a druggable vulnerability in therapeutic resistance. The findings may have potential applications in lymphoma, melanoma, and pancreatic cancer. This discovery is transformative for cancers beyond NSCLC.
“We hope that this environment will facilitate the initiation of a clinical trial based on these findings,” said Eichner, co-corresponding author of the study. The study is a success story for how basic discovery science can lead to therapeutic solutions.
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