Discovery of Treatment Mechanism May Improve Cancer Combination Therapy

Researchers recently discovered the mechanisms behind MEK inhibitors, which could lead to more optimal combination treatments for cancer.

In prior studies, the MEK inhibitor trametinib was shown to inhibit T cell responses in vitro, but was effective in tumor models. The drug is currently under evaluation for use in other cancers.

Trametinib was approved by the FDA for the treatment of BRAF-mutated melanoma, and has also been studied in combination with dabrafenib, a BRAF inhibitor.

MEK inhibitors target the MEK1/MEK2 enzymes, which affect the MAPK/ERK pathway that is overactive in certain cancers. This type of drug can be used to treat BRAF-mutated melanoma, and KRAS/BRAF mutated colorectal cancer.

In the current study published by Cancer Research, researchers discovered how trametinib is able to boost antitumor activity and inhibit cancer progression, even if it does not stop proliferation.

Small molecule kinase inhibitors are designed to target cancer-related mutations and proteins without harming surrounding healthy cells. Once these drugs began to receive approval for use in cancer, researchers began to study the effects of these treatments on the immune system.

“We realized that most small kinase inhibitors in the pipeline targeted pathways that are important for the function of immune cells,” said José R. Conejo-Garcia, MD, PhD. “However, they had been primarily tested in vitro against tumor cells or in immunodeficient animals at best. Very little was known about the consequences of using these interventions on spontaneous or immunotherapeutically boosted antitumor immunity.”

Researchers discovered that trametinib slows tumor progression by inhibiting the mobilization of myeloid-derived suppressor cells.

These cells increase during inflammation, infection, and cancer, and have the ability to stop T cell responses. Myeloid-derived suppressor cells are associated with treatment-resistance, according to the study.

A reduction in immune suppression that occurs when myeloid-derived suppressor cells are inhibited allows anti-cancer T cells to target the tumor. The efficacy of trametinib is contingent on the anti-cancer T cells, despite its inhibitory effects on this tumor cell compartment, according to the study.

While trametinib did not inhibit cancer cell proliferation, its effects on immune and non-immune compartments increased antitumor immunity. These effects were seen in vivo, and delayed cancer progression.

“Understanding the effects of trametinib on antitumor immunity is urgently needed to design the sequence of rational combinatorial interventions that include emerging and future anticancer immunotherapies,” Dr Conejo-Garcia said. “Our findings demonstrate that trametinib could be combined with existing immunotherapeutic agents in at least tumors that mobilize a significant amount of immunosuppressive myeloid cells.”