Researchers have already advocated intermittent treatments, either to provide a respite for example in the treatment of prostate cancer, or because models of cell ecology show the interest of pre-empting the development of the mutations of resistance.
Selumetinib, an experimental inhibitor of MEK 1/2 from AstraZeneca, has experienced numerous failures in its trials, including the most recent in non-small cell lung cancer (NSCLC) with KRAS mutation and thyroid cancer.
Despite this series of failures, selumetinib is still being tested in different types of cancer, both as monotherapy and in combination with checkpoint inhibitor drugs.
Nevertheless, the development of resistance has proven to be a problem with drugs that inhibit MEK and associated pathways. But the company is trying to turn these failures into opportunities by partnering with researchers at the Babraham Institute in the UK to figure out how cancer cells become resistant to treatment.
By studying the cellular signaling pathway that selumetinib was supposed to disrupt, the AZ-Babraham joint team discovered that the cancer cells were developing a bypass strategy to avoid the effects of the drug, but that this strategy was destroying the cancer cells when the drug was no longer applied.
The researchers made this discovery by exposing human colon cancer cells to selumetinib for several weeks. After a while, they became resistant to selumetinib by amplifying a gene called BRAF. This allowed them to maintain the production of growth factors.
But once the drug was removed, BRAF amplification became an obstacle, activating a pathway that caused rapid cancer cell cell aging. Apparently the amplification is not reversible and cells that do not have this mutation have a competitive advantage over cancer cells.
The researchers found that these cells were then susceptible to a second attack of selumetinib. They believe their findings would be applicable to melanoma and other cancers, they said.
Although in-vitro studies are rarely transposable to living beings, studies in mice have shown that intermittent administration can prolong the tumor's reduction effects of the drug.
It should be noted, however, that the mice had undergone xeno-grafting and therefore were not mice that would be models of the target cancer. Researchers believe that knowledge about resistance resistance should inform future dosing schedules.
They published their findings in the journal Nature Communications.
"Our results provide a clear rationale for intermittent drug therapy, to delay or defeat emerging resistance," they wrote in the study.