Mitogen-activated protein kinase kinase (MEK) is emerging as a possible new therapeutic target for the treatment of lung cancer, according to results from a recent study published in Cancer Research.
Researchers found that both tumor necrosis factor alpha (TNF?) and interferon gamma (IFN?) increase the sensitivity of lung cancer cells to MEK inhibitors such as trametinib, raising the possibility that treatment that combines immunotherapies—including checkpoint blockers—with MEK inhibitors may be effective in patients with lung cancer.
Seven MEK subtypes have been identified, and all mediate cellular responses to growth signals. Previous research has shown that when MEK is inhibited, apoptosis occurs and cell proliferation is blocked.
MEK is found on the KRAS pathway. This is significant because almost 30% of the 228,000 men and women who will be diagnosed with lung cancer this year will have a KRAS mutation, making their cancer more aggressive and difficult to treat. When functioning normally, KRAS controls cell proliferation. In KRAS-mutated lung cancers, cell proliferation remains unchecked.
Previously, researchers had found that combination therapy with trametinib, TNF? and IFN? brought about more cell apoptosis in patients with lung cancer than treatment with trametinib alone. IFN? is a cytokine crucial for anti-tumor immunity and enhances the anti-tumor activity of MEK inhibitors and TNF?.
In this study, lead author Amer A. Beg, PhD, senior member, Immunology Department, Lung Cancer Center of Excellence, Moffitt Cancer Center, Tampa, FL, and colleagues observed that MEK inhibitors work to increase the number of cell surface receptors that TNF? can bind to, leading to stronger and more sustained apoptosis signaling.
Dr. Beg and fellow researchers went on to assess the effects of a combination of MEK inhibitors with treatments known to increase TNF? and IFN? expression, to determine whether they could get an even better response.
After performing exome-wide gene expression studies in a KRAS-mutant human lung adenocarcinoma cell-line, they found that trametinib enhanced the expression of some TNF? target genes. It was upon combining TNF? with a MEK inhibitor, however, that they achieved the highest levels of gene expression.
MEK inhibitors also significantly increased the expression of TNF? and IFN? target genes, thus increasing anti-tumor immunity in mice given TNF? and IFN?.
“We conclude the MEK/ERK inhibitors can function to enhance TNF? + IFN? induced signaling responses. Furthermore, the multitude of MEK/ERK inhibitors identified suggest that on-target effects of these drugs are responsible for enhancement of TNF? + IFN? induced responses,” noted Dr. Beg and colleagues.
They also found that sensitivity to TNF? + IFN? and cooperation with MEK inhibitors occurred only in lung cancer cells, not melanoma.
Further, adding a PD-1 immune checkpoint inhibitor to MEK inhibitors brought about the strongest tumor regression.
“We found that the combination of PD-1 blockade and MEKi treatment resulted in profound tumor regression in all treated mice. While these results do not directly implicate roles for TNF? or IFN?, they nonetheless suggest that immunotherapeutics known to induce their expression can synergize with MEK [inhibitors] in induction of anti-tumor responses,” they added.
Future studies will be focused on the combination of MEK inhibitors and various other immune therapies such as CAR-T and adoptive T cell therapy.
“These studies will help determine if modulation of the immune microenvironment along with tumor signaling is a viable treatment strategy for lung cancer patients with KRAS mutations and potentially other mutations that rely on MEK signaling,” said first author Mengyu Xie, a cancer biology graduate student, Moffitt.
“Demonstrating that an anti-cancer agent can so effectively modulate the activity of a cytokine signaling pathway crucial for so many biological processes is conceptually novel and can lead to new understanding of oncogenic pathways and strategies for targeting them,” concluded Dr. Beg.
This work was supported by the Moffitt’s Miles for Moffitt event and Lung Cancer Center of Excellence, Prelude to a Cure, and the Department of Defense Lung Cancer Research Program.