Targeting mTOR to overcome resistance to hormone and CDK4/6 inhibitors in ER-positive breast cancer models

Abstract

Resistance to therapy remains a major obstacle in cancer management. Although treatment withhormone and CDK4/6 inhibitors is successful in luminal breast cancer, resistance to these treatmentsis frequent, highlighting the need for novel therapeutic strategies to delay disease progression andimprove patient survival. Here, we assessed the mechanisms of acquired resistance using T47Dand MCF-7 tamoxifen- and palbociclib-resistant cell-line variants in culture and as xenografts, andpatient-derived cells (PDCs) obtained from sensitive or resistant patient-derived xenografts (PDXs).In these models, we analyzed the efect of specifc kinase inhibitors on survival, signaling and cellularaggressiveness. Our results revealed that mTOR inhibition is more efective than PI3K inhibition inovercoming resistance, irrespective of PIK3CA mutation status, by decreasing cell proliferation andtumor growth, as well as reducing cell migration and stemness. Moreover, a combination of mTORand CDK4/6 inhibitors may prevent pathway reactivation downstream of PI3K, interfering with thesurvival of resistant cells and consequent tumor escape. In conclusion, we highlight the beneftsof incorporating mTOR inhibitors into the current therapy in ER+breast cancer. This alternativetherapeutic strategy not only enhances the antitumor response but may also delay the emergence ofresistance and tumor recurrence.