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 aren't available for all cancers, including non-small cell lung cancers (NSCLCs) that have a genetic mutation. A new study led by Northwestern University and the Salk Institute revealed two drugs, one FDA approved and the other in clinical trials, can be given in tandem to produce fewer and smaller tumors in mice with NSCLC.
The findings were published in Science Advances on March 17, 2023.
Lillian Eichner, an assistant professor of biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine, said the findings overcome former barriers that plague scientists in the search for effective therapies for NSCLCs with the LKB1 genetic mutation.
"A lot of drug targets are great, but as soon as you block them, something else comes in to compensate, which has been a major stumbling point," said Eichner, the co-corresponding and first author on the study. "You get this fundamental rewiring of the cellular machinery that circumnavigates the impact of the drug, and the patient doesn't get any benefit even though you've done a fantastic job inhibiting the target."
Roughly 20 percent of all NSCLCs have the LKB1 genetic mutation, and there are no effective targeted therapies currently on the market for patients with this cancer type.
"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," said Salk Institute Professor Reuben Shaw, senior and co-corresponding author of the study, and director of Salk's Cancer Center.
To create a therapy that could target the LKB1 mutation, the researchers turned to histone deacetylases (HDACs). HDACs are proteins associated with tumor growth in solid tumors. Several HDAC-inhibitor drugs are already FDA approved (safe for human use) for specific forms of lymphoma, but data on their efficacy in solid tumors or whether tumors bearing specific genetic alterations may exhibit heightened therapeutic potential has been lacking.
Based on previous findings connecting the LKB1 gene to three other HDACs that all rely on HDAC3, the team started by conducting a genetic analysis of HDAC3 in mouse models of NSCLC, discovering an unexpectedly critical role for HDAC3 in multiple models. After establishing that HDAC3 was critical for the growth of the difficult-to-treat LKB1-mutant tumors, the researchers next examined whether pharmacologically blocking HDAC3 could give 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 a different class of enzymes related to cancer). Tumors often become quickly resistant to trametinib, but co-treatment with a drug that inhibits a known protein helps reduce this resistance. Because that protein relies on HDAC3, the researchers believed that a drug that targets HDAC3 - like entinostat - would help manage trametinib resistance, too.
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 percent less tumor volume and 63 percent fewer tumors in their lungs than the untreated mice. Additionally, the team confirmed that entinostat was a viable treatment option in cases where a tumor was resistant to trametinib.
"We thought a subgroup of HDAC enzymes were directly linked to the cause of LKB1 mutant lung cancer. But we didn't know the specific role of HDAC3 in lung tumor growth," Eichner said. "We've now shown that HDAC3 is essential in lung cancer, and that it is a druggable vulnerability in 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, the scientists see this discovery as transformative for cancers beyond NSCLC, with potential applications in lymphoma, melanoma and pancreatic cancer.
"My independent laboratory is fortunate to be part of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, which is very supportive of translational research," Eichner said. "We hope that this environment will facilitate the initiation of a clinical trial based on these findings."
Other authors include Caroline K. McGuire and Irena Gushterova of Northwestern; and Stephanie D. Curtis, Sonja N. Brun, Joshua T. Baumgart, Elijah Trefts, Debbie S. Ross and Tammy J. Rymoff of Salk.
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 (PF-15-037-01-DMC), and Chapman Foundation.
