Drug Combination Seeks to Prevent Endocrine Resistance in Breast Cancer

The combination of selinexor and 4-OHT may be able to prevent endocrine resistance in hormone-responsive breast cancer by rewiring gene pathways.

The combination of selinexor and 4-OHT may prevent endocrine resistance in patients with breast cancer by reprogramming tumor genes, according to a new study published in Cancers.

Endocrine resistance is a common cause of hormone-responsive breast cancer-related deaths among women with the disease. Although endocrine therapy is the most effective treatment for hormone-responsive breast cancer, some patients will not respond to treatment or develop resistance to these drugs over time, the study authors noted.

In the study, the researchers aimed to determine whether treatment with the combination of selinexor and 4-OHT would be more effective preventing endocrine resistance than either drug alone. Selinexor, which has been evaluated in multiple late-stage clinical trials in patients with relapsed and/or refractory hematological and solid tumor malignancies, prevents XPO1 anti-cancer proteins from functioning and 4-OHT inhibits estrogen receptors from responding to the hormone.

Prior research shows that women who expressed higher levels of XPO1 and a “signature” of other nuclear transport genes were more likely to be endocrine resistant, according to the current study. The authors suggested that XPO1 and hormone receptor Era, which is responsive to estrogen and expressed in 70% of all breast cancers, may work together to promote endocrine resistance.

To test their hypothesis about the combination therapy, the researchers treated endocrine-resistant tumor cells with either selinexor or 4-OHT monotherapy or with the combination of both in human breast tumor cells implanted in mice.

Overall, the study found that the combination of selinexor and 4-OHT caused the tumors to regress faster and more completely than either drug alone, and this effect continued for several weeks following treatment. The study also showed that drug combination was more effective than either drug alone at reducing the tumor cells’ viability. Additionally, the authors found that the drug combination increased the expression of more than 100 genes and decreased the expression of 132 other genes that were not affected by either drug alone.

According to the researchers, the combination treatment led to the decreased activity of genes that were associated with endocrine resistance and metastases, causing sustained tumor regression. This included a set of genes regulated by the protein Akt, which controls cellular survival, proliferation, and migration.

The findings demonstrated that combined targeting of XPO1 and Era rewired the metabolic pathways to regenerate new vulnerabilities in endocrine-resistant breast tumors, the researchers concluded.

References

Kulkoyluoglu-Cotul E, Smith BP, Wrobel K, et al. Combined targeting of estrogen receptor alpha and XPO1 prevent Akt activation, remodel metabolic pathways and induce autophagy to overcome tamoxifen resistance. Cancers. 2019. https://doi.org/10.3390/cancers11040479