New combination of drugs works together to reduce lung tumors in mice

Cancer treatments have long been geared toward personalization—finding the right drug that works for a patient’s unique tumor, based on specific genetic and molecular patterns. Many of these targeted therapies are highly effective, but are not available for all cancers, including non-small cell lung cancer (NSCLC) with mutations in the LKB1 gene.

A new study led by Salk Institute Professor Reuben Shaw and former postdoctoral fellow Lillian Eichner, now an assistant professor at Northwestern University, has revealed trametinib and entinostat are FDA-approved (currently under FDA approval). clinical trials) can be used in parallel for fewer and smaller productions. tumors in mice with LKB1 mutant NSCLC.

The findings were published in scientific advance on March 17, 2023.

“For non-small cell lung cancer cases with LKB1 mutations, standard chemotherapy and immunotherapy treatments are not effective,” said Shaw, senior author and co-author of the study. researcher, and director of Salk’s Cancer Center. “Our findings demonstrate that there is a way to target these cases using FDA-approved or clinically tested drugs, so this work could easily be done.” for clinical trial use in humans.”

About 20 percent of all NSCLCs have mutations in the LKB1 gene, which means that there are no effective targeted therapies currently on the market for patients with this type of cancer. To create a therapy that can target the LKB1 mutation, the researchers turned to histone deacetylase (HDAC). HDACs are proteins that bind to tumor growth and cancer metastasis, with characteristic overexpression in solid tumor.

Several HDAC inhibitors have been approved (safe for human use) by the FDA for specific forms of lymphoma, but there is a lack of data on their effectiveness in solid tumors or whether the Tumors carrying specific genetic mutations may exhibit high therapeutic potential.

Building on previous findings linking the LKB1 gene with three other HDACs, all of which are HDAC-based, the team began by conducting genomic analysis of HDAC3 in mouse models of NSCLC, discovering The unexpected important role of HDAC3 in many models. Having established that HDAC3 is important for the development of difficult-to-treat LKB1 mutant tumors, the researchers next examined whether pharmacological blocking of HDAC3 could have an effect. equally strong or not.

The team is curious about testing two drugs, entinostat (an HDAC inhibitor that in clinical trials is known to target HDAC1 and HDAC3) and FDA-approved trametinib (an inhibitor of another enzyme linked to HDAC). related to cancer). Tumors often quickly become resistant to trametinib, but concomitant treatment with a drug that inhibits the downstream protein of HDAC3 will help reduce this resistance.

Because that protein depends on HDAC3, the researchers believe that a drug that targets HDAC3—like entinostat—would also help manage trametinib resistance.

After treating mice with LKB1 mutant lung cancer with different treatment regimens for 42 days, the team found that the mice given both entinostat and trametinib experienced a 79% reduction. tumor The volume and tumor volume in their lungs were 63% less than that of untreated mice. In addition, the team confirmed that entinostat is a viable treatment option in cases of trametinib-resistant tumors.

“We think that the entire class of HDAC enzymes is directly involved in the etiology of LKB1 mutant lung cancer, but we do not know the specific role of HDAC3 in lung tumor development,” the authors said. first and co-author Eichner said. “We have now shown that HDAC3 is essential in lung cancer and that it is a treatable gap in therapeutic resistance.”

These findings could lead to clinical trials to test new treatment regimens in humans, as entinostat is already in use. clinical trials and trametinib is FDA approved. Importantly, Shaw sees this discovery as a turning point for cancers beyond NSCLC, with potential applications in lymphoma, melanoma, and pancreas. cancer.

“Our lab has been committed to this project for many years, taking small, meaningful steps to achieve these findings,” said Shaw, who holds the William R. Brody Chair. . “This is truly a success story about how fundamental discovery science can lead to therapeutic solutions in the not-too-distant future.”

“My independent laboratory is fortunate to be part of the Lurie Cancer Center at Northwestern University Feinberg School of Medicine, which greatly supports translational research. We hope that this environment will facilitate the initiation of clinical trials based on these findings,” said Eichner.