AstraZeneca’s experimental MEK 1/2 inhibitor selumetinib has racked up its share of trial failures, most recently in KRAS mutation-positive non-small cell lung cancer (NSCLC) and thyroid cancer. But the company is turning the disappointments into an opportunity, teaming up with researchers at the Babraham Institute in the United Kingdom to try to determine how cancer cells become resistant to the treatment.
By studying the cell signaling pathway that selumetinib was designed to disrupt, the AZ-Babraham team discovered that cancer cells eventually develop a workaround strategy to evade the drug’s effects—but that the very same strategy actually kills cancer cells when the drug is withdrawn. They published their findings in the journal Nature Communications.
Selumetinib inhibits the RAS-BRAF-MEK-ERK signaling pathway, which facilitates the growth and division of cancer cells. The discovery that stopping the drug actually helps promote cancer-cell death could change how MEK inhibitors and other medicines that target the pathway are used in the treatment of the disease, said AstraZeneca researcher Paul Smith in a statement.
The researchers made the discovery by exposing human colon cancer cells to selumetinib over several weeks, at which point they became resistant by amplifying a gene called BRAF. That, in turn, allowed them to maintain growth signals. But once the drug was withdrawn, BRAF amplification became an impediment, activating a pathway that caused the cancer cells to rapidly age and to stop growing.
Those cells then became sensitive to a second attack of selumetinib, the researchers discovered. They believe their findings would be applicable to melanoma and other cancers, they said.
Despite a string of failures, selumetinib is still very much alive. In fact, AstraZeneca and Merck teamed up in the summer of 2017 to co-develop the drug and PARP inhibitor Lynparza. Last month, the two companies announced they received breakthrough-therapy designation from the FDA for selumetinib in a rare, pediatric genetic condition called NF1 plexiform neurofibromas. Merck and AstraZeneca continue to study selumetinib in a variety of cancers, both as a solo therapy and in combination with checkpoint-inhibiting drugs, they said in a statement at the time.
Still, resistance has proven to be a problem with drugs that inhibit MEK and related pathways. Mouse studies have shown that intermittent dosing can prolong the drugs’ tumor-shrinking effects, the AZ-Babraham team noted in the new study. And the researchers believe that the insight they gained into how resistance occurs should inform dosing regimens going forward.
“Our results provide a clear rationale for intermittent treatment (drug holidays), to delay or overcome emergent resistance,” they wrote in the study.