Cancer treatments have long been moving towards 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 they are not available for all types of cancer, including non-small cell lung cancers (NSCLCs) that have an LKB1 gene mutation. A new study led by Salk Institute professor Robin Shaw and former postdoctoral fellow Lillian Eichner, now an assistant professor at Northwestern University, finds that FDA-approved tramutinib and intenostat (which is currently in clinical trials) can be given in combination to produce a number of Less and smaller. Tumors in mice with LKB1-mutant NSCLC.
The results are published in Science advances On March 17, 2023.
“For cases of non-small cell lung cancer with an LKB1 mutation, standard chemotherapy and immunotherapy are not effective,” says Xu, senior author of the study and director of the Salk Cancer Center. “Our findings show that there is a way to target these conditions using drugs that are FDA-approved or already in clinical trials, so this work could easily be used in a human clinical trial.”
Approximately 20 percent of all non-small cell carcinomas have the LKB1 gene mutation, which means that there are no effective targeted therapies currently on the market for patients with this type of cancer. To create a treatment 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 inhibitor drugs are already FDA-approved (safe for human use) for certain forms of lymphoma, but data on their efficacy in solid tumors or whether tumors carrying specific genetic alterations might show increased therapeutic potential has been lacking.
Building on previous findings linking the LKB1 gene to three other HDACs that are all dependent on HDAC3, the team set out to perform a genetic analysis of HDAC3 in murine models of NSCLC, discovering an unexpectedly critical role for HDAC3 in multiple models. Having established that HDAC3 was crucial for the growth of hard-to-treat LKB1 mutant tumours, the researchers next examined whether pharmacological blocking of HDAC3 could confer a similarly potent effect.
The team was interested in testing two drugs, entinostat (an HDAC inhibitor in clinical trials known to target HDAC1 and HDAC3) and the FDA-approved trametinib (an inhibitor of a different class of enzymes related to cancer). Tumors often rapidly become resistant to trametinib, but combined treatment with a drug that inhibits a protein downstream of HDAC3 helps reduce this resistance. Because this protein is dependent on HDAC3, the researchers thought that a drug that targets HDAC3 — such as entinostat — would help manage trametinib resistance, too.
After treating mice with LKB1-mutated lung cancer with altered 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 untreated mice. In addition, the team confirmed that entinostat was a viable treatment option in cases where the tumor was resistant to trametinib.
“We thought that the entire HDAC enzyme class was directly related to the causation of LKB1 mutant lung cancer. But we did not know the specific role of HDAC3 in lung tumor growth,” said first author and co-author Eichner. “We have now shown that HDAC3 is essential for lung cancer, and that it represents a drugable 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, Xu sees this discovery as transformative for cancers beyond NSCLC, with potential applications in lymphoma, melanoma and pancreatic cancer.
“This is truly a success story of how the science of basic discovery could lead to therapeutic solutions in the not-too-distant future,” says Shaw, holder of the William R. Chair.
“My independent lab is fortunate to be part of the Lury Cancer Center at Northwestern University’s Feinberg School of Medicine, and is very supportive of translational research. We hope that this environment will make it easier to start a clinical trial based on these findings,” says Eichner.
Other authors include Stephanie D. Curtis, Sonya N. Brun, and Joshua T. 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, CCSG P30CA23100), the Leona M. and Harry B. Society (PF-15-037-01-DMC) and the Chapman Foundation.
