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 with hormone and CDK4/6 inhibitors is successful in luminal breast cancer, resistance to these treatments is frequent, highlighting the need for novel therapeutic strategies to delay disease progression and improve patient survival. Here, we assessed the mechanisms of acquired resistance using T47D and MCF-7 tamoxifen- and palbociclib-resistant cell-line variants in culture and as xenografts, and patient-derived cells (PDCs) obtained from sensitive or resistant patient-derived xenografts (PDXs). In these models, we analyzed the effect of specific kinase inhibitors on survival, signaling and cellular aggressiveness. Our results revealed that mTOR inhibition is more effective than PI3K inhibition in overcoming resistance, irrespective of PIK3CA mutation status, by decreasing cell proliferation and tumor growth, as well as reducing cell migration and stemness. Moreover, a combination of mTOR and CDK4/6 inhibitors may prevent pathway reactivation downstream of PI3K, interfering with the survival of resistant cells and consequent tumor escape. In conclusion, we highlight the benefits of incorporating mTOR inhibitors into the current therapy in ER + breast cancer. This alternative therapeutic strategy not only enhances the antitumor response but may also delay the emergence of resistance and tumor recurrence.

A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer

“…mTORC1 inhibitors have been studied in combination with hormone therapy and/or CDK4/6 inhibitors in melanoma and breast cancer, although the exact mechanisms remain unclear [ 33 , 34 ]. In ER+ breast cancer, combined inhibition of mTOR and CDK4/6 may result in more complete suppression of E2F-dependent transcription [ 35 ] and in our study palbociclib-resistant cell lines demonstrated a loss of RB1 expression and increase of Cyclin E1, both of which can enhance E2F activity and likely contributed to resistance to CDK4/6 inhibition.…”

Role of hydroxymethylglutharyl-coenzyme A reductase in the induction of stem-like states in breast cancer

“…Alterations in lipid metabolism have gained attention as main players in many aspects of cancer growth, including cancer stem cells (CSCs) states. Indeed, hypercholesterolemia can lead to cancer by several means, including cholesterol derived-oncometabolites (Silvente-Poirot et al 2018 ), or an increased but regulated uptake of cholesterol in the form of low-density lipoprotein (LDL)-cholesterol (Scully et al 2022 ). In addition, enhanced endogenous biosynthesis of cholesterol and isoprenoids appears to play a role in cancer initiation and progression (Göbel et al 2022 ), since many enzymes in the mevalonic acid (MVA) pathway such as 3-hydroxy-3methylglutaryl-coenzyme A reductase (HMGCR), farnesyl diphosphate synthase, geranylgeranyl pyrophosphate synthase, squalene synthase and squalene epoxidase are overexpressed and overactivated in melanoma (Kuzu et al 2016 ), glioblastoma (Abate et al 2017 ), lung (Wang et al 2018 ), colon (Gao et al 2021 ), prostate (Todenhöfer et al 2013 ), ovarian (de Wolf et al 2017 ) and breast cancer (BC) (Brown et al 2016 ).…”

Manuka Honey Inhibits Human Breast Cancer Progression in Preclinical Models

“…This effect is mediated in part by inhibition of downstream phosphoinositide 3 kinase (PI3K) AKT/mammalian target of rapamycin (mtTOR) signaling pathway. Blockade of PI3K/AKT/mTOR signaling has been shown to be effective in overcoming resistance in ER+ BC [37]. Antioxidant properties of Manuka honey have been attributed to its uniquely high content of polyphenols such as caffeic acid, caffeic acid phenethyl ester (CAPE) chrisin, etc, known to activate AMPK and inhibit the PI3K/AKT/mTOR pathways [38][39][40].…”