Homing in on one HDAC might be key to success in currently untreatable lung cancer

Though there are four histone deacetylase (HDAC) inhibitors that are FDA approved to treat some forms of lymphoma, there’s less evidence for their efficacy in solid tumors. Now, new findings in mice suggest that homing in on one HDAC in particular may have therapeutic potential against a currently untreatable form of non-small cell lung cancer, or NSCLC.

In a study published March 17 in Science Advances, researchers from the Salk Institute described how pairing an investigational-stage HDAC inhibitor with an FDA-approved drug reduced both the size and number of tumors in mice with LKB1-mutated NSCLC, a subtype that makes up around 20 percent of NSCLC cases. The team is now taking the first steps to initiate clinical trials in humans.

“For non-small cell lung cancer cases with the LKB1 mutation, standard chemotherapy and immunotherapy treatments are not effective,” senior and co-corresponding author Reuben Shaw, Ph.D., Director of Salk's Cancer Center, said in a press release. “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.”

The new study builds on recent research that suggests a genetic link between HDACs and the LKB1 gene. In general, HDACs help regulate gene expression. In the context of cancer, they’re associated with tumor growth and metastasis. One HDAC enzyme, HDAC3, seems to be necessary for the function of the other HDACs linked to the LKB1 gene, the researchers explained in the paper. But few animal studies have looked at the activity of individual HDACs; the approved HDAC inhibitors work against multiple HDACs, rather than any one of them specifically. Given HDAC3’s importance to the function of other enzymes and the link between HDACs and LKB1, the researchers decided to analyze its role in NSCLC.

To do that, they turned to genetically engineered mouse models of LKB1-mutated NSCLC. Studies on tumor formation in the mice revealed that HDAC3 was “of critical importance” to tumor growth, the researchers wrote: The mice that lacked the gene for HDAC3 had smaller tumors, slower tumor growth and a trend towards fewer tumors.

Armed with these results, they then set out to see if blocking HDAC3 with a drug could have the same effect. For this they turned to entinostat, an HDAC inhibitor that targets HDAC3 and another HDAC in the same family, HDAC1, and Novartis’ MEK inhibitor trametinib, trade name Mekinist. Entinostat was developed by Syndax and was previously studied in combination with a PD-1 inhibitor in clinical trials for breast and ovarian cancer. Trametinib is approved for several cancer types including one subtype of NSCLC, but tumors rapidly develop resistance to it.

Genetic analyses suggested that trametinib resistance could be overcome by inhibiting HDAC3, indicating that the two drugs might make a good pair in LKB1-mutated NSCLC. To find out, the researchers gave mouse models with the cancer type one of three different regimens for 42 days: entinostat alone, trametinib alone or the two drugs together. While neither entinostat nor trametinib alone shrank the tumors or stopped them from growing, the mice that were treated with the two drugs together showed 79% lower tumor volume and 63% fewer tumors than untreated controls.

“These data identified that entinostat and trametinib, which are both clinically viable drugs that do not elicit efficacy as single-agent treatments for lung cancer, impart therapeutic efficacy in the [LKB1-mutated NSCLC] model when administered simultaneously,” the researchers wrote in the paper.

Efforts to initiate a clinical trial on the regimen in patients with LKB1-mutated NSCLC are underway at Northwestern University's Feinberg School of Medicine, where first author Lillian Eichner, Ph.D., is an now assistant professor, Shaw told Fierce Biotech Research in an email. Meanwhile, other animal studies on HDAC3 in melanoma, pancreatic cancer and other tumor types suggest that it could help overcome trametinib resistance in those cases, too.

Editor's note: A previous version of this article incorrectly described trametinib as a chemotherapy.