A new study led by Salk Institute professor Reuben Shaw and former postdoctoral fellow Lillian Eichner, now an assistant professor at Northwestern University, has discovered a drug combination that may shrink non-small cell lung tumors (NSCP) who have an LKB1 gene mutation.
The study, published in Science Advances, revealed that the trametinib and entinostatboth FDA-approved and currently in clinical trials, can be administered together to produce fewer and smaller tumors in LKB1-mutant NSCLC mice.
NSCLC tumors with the LKB1 gene mutation have no effective targeted therapies on the market at present. Therefore, to find a therapy that could target this mutation, the researchers turned to histone deacetylases (HDACs).
HDAC inhibitors are proteins associated with tumor growth and cancer metastasis, and there are several HDAC inhibitor drugs that are already FDA-approved for specific forms of lymphoma. However, data on its efficacy in solid tumors or whether tumors that have specific genetic alterations may exhibit greater therapeutic potential are lacking.
The researchers began by performing a genetic analysis of HDAC3 in mouse models of NSCLC, and discovered an unexpectedly critical role for HDAC3 in multiple models.
After establishing that HDAC3 was essential for the growth of difficult-to-treat LKB1 mutant tumors, the researchers examined whether pharmacological blockade of HDAC3 could have a similarly potent effect.
The team was curious about try two drugs, entinostat (an HDAC inhibitor in clinical trials known to target HDAC1 and HDAC3) and trametinib FDA-approved (an inhibitor of a different class of enzymes linked to cancer).
Tumors often quickly become resistant to trametinib, but co-treatment with a drug that inhibits a protein downstream of HDAC3 helps reduce this resistance.
Because that protein is based on HDAC3, the researchers believed that a drug that targets HDAC3, such as entinostat, would also help control resistance to trametinib.
After treating mice with LKB1 mutation-positive lung cancer with varying treatment regimens for 42 days, the team found that mice that given entinostat and trametinib had 79% less tumor volume and 63% less tumors in the lungs than untreated mice.
In addition, the team confirmed that entinostat was a viable treatment option in cases where a tumor was resistant.
The study is promising because it offers a treatment option for a specific type of lung cancer that currently has no effective targeted therapies. In addition, the drugs used in the study are already FDA-approved and in clinical trials, which means they could be available for use in humans more quickly.
However, as lead author Reuben Shaw points out, human clinical trials will be needed to confirm the efficacy of the combination of trametinib and entinostat in patients with LKB1-mutated NSCLC. Although the results in mice are promising, clinical trials in humans are essential to assess the safety and efficacy of a treatment.
