Drug Combination Overcomes Chemotherapy Resistance in Triple Negative Breast Cancer

Researchers pinpoint method to reverse cancer cell resistance to chemotherapy.

With traditional chemotherapy drugs showing long term effectiveness in just 20% of triple negative breast cancer patients, researchers may have found a method to overcome cancer cell resistance to chemotherapy.

In a study published online in the journal Proceedings of the National Academy of Sciences on December 1, 2014, researchers from The Johns Hopkins University may have discovered how breast cancer cells resist chemotherapy and how to reverse that resistance.

Triple negative breast cancers contain a high number of breast cancer stem cells, which exhibit a significantly higher level of activity from the numerous genes controlled by the protein hypoxia-inducible factor (HIF). As a result, the researchers sought to evaluate whether HIF inhibitors could improve the effectiveness of chemotherapy.

“Our study showed that chemotherapy turns on HIF and that HIF enhances the survival of breast cancer stem cells, which are the cancer cells that must be killed to prevent relapse and metastasis,” said lead researcher Gregg Semenza, MD, PhD, in a press release. “The good news is that we have drugs that block HIF from acting.”

The researchers treated lab-grown triple negative breast cancer cells with the chemotherapy drug paclitaxel to evaluate changes in HIF levels. The HIF protein and activity levels increased after 4 days, but so did the percentage of breast cancer stem cells among the surviving cells.

After the researchers genetically altered the cancer cells to have less HIF, the disease’s stem cells were no longer protected from chemotherapy, which shows that HIF is needed for stem cells to resist the toxic effects of chemotherapy.

The researchers determined that HIF enhances the survival of the stem cells by increasing the levels of multidrug resistance protein 1 (MDR1), which expels the chemotherapy drug from cancer cells. When paclitaxel was combined with the HIF inhibitor digoxin, however, the MDR1 levels decreased instead of increasing.

In mice implanted with triple-negative breast cancer cells, the digoxin and paclitaxel combination was found to shrink the tumor size by 30% more than treatment with paclitaxel alone, in addition to decreasing the number of breast cancer stem cells and the levels of MDR1.

Treatment with digoxin and the chemotherapy drug gemcitabine reduced tumor volume to zero within 3 weeks and prevented the immediate relapse shown in mice treated with gemcitabine alone at the end of treatment.

Patient databases showed that among triple negative breast cancer patients treated with chemotherapy, women with higher than average HIF activity levels in their tumor were much more likely to die of the disease than those with lower than average HIF levels.

The researchers noted that if their work is reinforced during clinical trials, it may allow the identification of potentially unresponsive patients before treatment, at which point they can be given a more effective combination therapy.