Warfarin-Like Drug Reverses Tamoxifen Resistance in Breast Cancer

Cancer is known to constantly develop new ways to evade treatment and become drug-resistant. Treatment-resistant cancer cells are particularly dangerous because they can spread throughout the body, which has presented a continuous challenge in achieving remission.

Specifically, approximately half of patients treated with tamoxifen, an estrogen receptor-blocker, become resistant to the treatment. For these patients, the cancer returns, and they must seek treatment with another drug to achieve remission.

In a new study published by Oncotarget, the authors examined potential avenues breast cancer cells take to resist tamoxifen and what role the drug may play in resistance.

The scientists assessed whether tamoxifen resistance is related to mitochondria, and discovered that the NQ01 protein triggers the decision if a cancer cell survives treatment or not.

“In simple terms, the process of poisoning the cell (with tamoxifen) actually has the opposite effect, stimulating the cancer cells to respond by revving their engines in order to survive,” said researcher Michael P Lisanti, MD, PhD.

In the study, the authors tested normal and drug-resistant cells to demonstrate if the mitochondria is manipulated to increase survival. They found that mitochondrial power distinguished the cell types, according to the study.

After this discovery, the authors used an approach that combined protein profiling, genetics, and metabolism to determine the genes involved with drug resistance. Interestingly, the addition of the NQ01 protein alone would allow the cells to survive.

To further test their theory, the tamoxifen-resistant cells were challenged with an NQ01 inhibitor. The drug, dicoumarol, is a vitamin K antagonist like warfarin. The authors found that treating drug-resistant cells with dicoumarol re-sensitized the cells to therapy, essentially reversing resistance.

“This is the first evidence that tamoxifen resistance is related to a specific metabolic behaviour [sic], ie. increased mitochondrial power, which is important because this is not related to tamoxifen’s effect on the estrogen receptor,” Dr Lisanti said. “It also confirms that tamoxifen resistance is not a mechanism related to estrogen.”

These findings provide hope that patients who develop resistance to tamoxifen and experience relapse could be treated with dicoumarol or a related drug and continue on therapy. Since dicoumarol has already been approved, the time to clinical use among breast cancer patients may be expedited.

“Now that we have identified the target, this will allow us and others to design new drugs to overcome tamoxifen resistance,” said researcher Marco Fiorillo, PhD. “There are already existing experimental drugs for targeting NQO1 and GCLC, for other reasons, so making inhibitors to target these enzymes is a practical reality.”