Acquired resistance mechanisms to aromatase inhibitors and new targets/drugs to improve ER+ breast cancer therapy
The main therapeutic approach for hormone-dependent breast cancer is the use of aromatase inhibitors (AIs). Despite their therapeutic success, the AIs used in the clinic induce some adverse effects, being the major clinical concern the development of endocrine resistance. Therefore, it is of great interest to discover new drugs or strategies to improve therapy and overcome resistance. In this context, our group has focused on the design/synthesis and anti-tumor activity of the new molecules, as potential and more effective AIs with fewer adverse effects.
These studies unveilled the structural modifications in steroidal scaffold that are translated into better aromatase inhibition and anti-tumor properties, providing important information for the rational design/synthesis of more effective AIs. On the other hand, the group has also studied the mechanisms underlying the biological action of the AIs used in the clinic in hormone-sensitive breast cancer cells and also the mechanisms associated to the AIs-acquired resistance.
These studies highlighted new therapeutic strategies/targets that together with aromatase inhibition may improve breast cancer therapy, overcoming AIs-acquired resistance.
Recent research have demonstrated that autophagy is mechanism of exemestane-acquired resistance and that by targeting PI3K or androgen receptor (AR) it is possible to improve exemestane therapy and surpass exemestane-resistance.
The potential clinical benefit of targeting androgen receptor (AR) in estrogen-receptor positive breast cancer cells treated with Exemestane.
Amaral C., Augusto T., Almada M., Cunha S.C., Correia-da-Silva G., Teixeira N.
Biochim Biophys Acta Mol Basis Dis. 1866(5):165661. 2020
Effects of new C6-substituted steroidal aromatase inhibitors in hormone-sensitive breast cancer cells: Cell death mechanisms and modulation of estrogen and androgen receptors.
Augusto T., Amaral C., Varela C.L., Bernardo F., Tavares da Silva E., Roleira F. M. F., Costa S., Teixeira N., Correia-da-Silva G.
Journal of Steroid Biochemistry and Molecular Biology 195: 105486. 2019
Hormone-dependent breast cancer: Targeting autophagy and PI3K overcomes Exemestane-acquired resistance.
Amaral C., Augusto T., Tavares-da-Silva E., Roleira F. M. F., Correia-da-Silva G., Teixeira N.
Journal of Steroid Biochemistry and Molecular Biology 183:51-61. 2018