by Cancer treatments have long moved toward personalization — finding the right drugs that work 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 cancers (NSCLCs) with an LKB1 genetic mutation. A new study led by Reuben Shaw, a professor at the Salk Institute, and former postdoctoral researcher Lillian Eichner, now an assistant professor at Northwestern University, revealed that FDA-approved trametinib and entinostat (which are currently in clinical trials) can work together. are given to fewer and smaller tumors in mice with LKB1-mutated NSCLC.
The findings have been published in Scientific progress on March 17, 2023.
“For cases of non-small cell lung cancer with the LKB1 mutation, standard chemotherapy and immunotherapy treatments are not effective,” said Shaw, the study’s senior and co-corresponding author, and director of Salk’s Cancer Center. “Our findings show that there is a way to address these cases with drugs that are FDA-approved or already in clinical trials, so this work could easily be used for a human clinical trial.”
About 20 percent of all NSCLCs have the LKB1 genetic mutation, meaning there are currently no effective targeted therapies on the market for patients with this type of cancer. To create a therapy that could target the LKB1 mutation, the researchers turned to histone deacetylases (HDACs). HDACs are proteins associated with tumor growth and cancer metastasis, with characteristic overexpression in solid tumors. Several HDAC inhibitors are already FDA-approved (safe for human use) for specific forms of lymphoma, but data on their efficacy in solid tumors or whether tumors with specific genetic alterations may show increased therapeutic potential are lacking.
Based on previous findings linking the LKB1 gene to three other HDACs that all depend on HDAC3, the team began performing a genetic analysis of HDAC3 in mouse models of NSCLC, identifying an unexpectedly critical role for HDAC3 in multiple models. discovers. Having determined that HDAC3 was crucial to the growth of the hard-to-treat LKB1-mutated tumors, the researchers next investigated whether pharmacologically blocking HDAC3 could produce a similarly potent effect.
The team was curious about testing two drugs, entinostat (an HDAC inhibitor in clinical trials known to target HDAC1 and HDAC3) and FDA-approved trametinib (an inhibitor for another class of enzymes related to with cancer). Tumors often quickly become resistant to trametinib, but concomitant treatment with a drug that inhibits a protein downstream of HDAC3 helps to reduce this resistance. Because that protein is dependent on HDAC3, the researchers believed that a drug that targets HDAC3 – such as entinostat – would also help control trametinib resistance.
After 42 days of treating mice with LKB1-mutated lung cancer with variable treatment regimens, the team found that mice given both entinostat and trametinib had 79 percent less tumor volume and 63 percent fewer tumors in their lungs than the untreated mice. In addition, the team confirmed that entinostat was a viable treatment option in cases where a tumor was resistant to trametinib.
“We thought that the entire HDAC enzyme class was directly related to the cause of LKB1-mutated lung cancer, but we did not know the specific role of HDAC3 in lung tumor growth,” says first and co-corresponding author Eichner. “We have now shown that HDAC3 is essential in lung cancer, and that it is a vulnerability to therapeutic resistance.”
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. Importantly, Shaw sees this discovery as transformative for cancers beyond NSCLC, with potential applications in lymphoma, melanoma and pancreatic cancer.
“Our lab has devoted years to this project and has taken small and meaningful steps toward these findings,” said Shaw, holder of the William R. Brody Chair. “This is truly a success story for how basic discovery science can lead to therapeutic solutions in the not-so-distant future.”
“My independent laboratory is fortunate to be part of the Lurie Cancer Center at Northwestern University’s Feinberg School of Medicine, which is very supportive of translational research. We hope that this environment will facilitate the initiation of a clinical trial based on these findings. facilitate,” says Eichner.
Other authors include Stephanie D. Curtis, Sonja N. Brun, Joshua T. Baumgart, Elijah Trefts, Debbie S. Ross, and Tammy J. Rymoff van Salk; and Caroline K. McGuire and Irena Gushterova of Northwestern University.
The work was supported by the National Institutes of Health (R35CA220538, P01CA120964, K22CA251636, 5T32CA009370, 5F32CA206400, CCSG P30CA014195 and CCSG P30CA23100), Leona M. and Harry B. Helmsley Charitable Trust (#2012-PG-MED002), American Cancer Society (#2012-PG-MED002), (PF-15-037-01-DMC) and Chapman Foundation.
