Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling

Beeram, M.; Tan, Qing; Tekmal, Rajeshwar Rao; Russell, Douglas; Middleton, A.; deGraffenried, Linda A.

doi:10.1093/annonc/mdm170

Cited by 158 publications

(98 citation statements)

References 19 publications

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“…Activation of AKT and overexpression of EGF and ERBB receptors are consistent with previous observations in MCF7-LTED cells and related breast cancer conditions (Masamura et al, 1995;Jeng et al, 1998;Shim et al, 2000;McClelland et al, 2001;Knowlden et al, 2003;Osborne et al, 2005;Yue et al, 2005;Song et al, 2006;Beeram et al, 2007;LewisWambi et al, 2008;Santen et al, 2008;Ghayad et al, 2009). Notably, ERBB2 amplification was associated with resistance to endocrine therapies (Ellis et al, 2006), and treatment with the mTOR inhibitor RAD001 increased letrozole efficacy in a neoadjuvant setting of ERa-positive breast cancer (Baselga et al, 2009).…”

Section: Resultssupporting

confidence: 85%

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

et al. 2010

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Endocrine therapies targeting the proliferative effect of 17b-estradiol through estrogen receptor a (ERa) are the most effective systemic treatment of ERa-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through molecular mechanisms that are not yet fully understood. The longterm estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERa. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were predicted to be influenced by transcription factors known to be involved in acquired resistance or cell proliferation (for example, interferon regulatory transcription factor 1 and E2F1, respectively) but, notably, not by canonical ERa transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)-to pS167-ERa were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERa-negative status, early response to letrozole and tamoxifen, and recurrence after tamoxifen treatment. In accordance with these profiles, MCF7-LTED cells showed increased sensitivity to inhibition of FGFR-mediated signaling with PD173074. This study provides mechanistic insight into acquired resistance to endocrine therapies of breast cancer and highlights a potential therapeutic strategy.

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Section: Resultssupporting

confidence: 85%

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

et al. 2010

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“…A potential mechanism of endocrine resistance is aberrant signaling through the PI3K signaling pathway (17,25). Preclinical studies have shown that breast cancer cells with upregulated AKT signaling are resistant to ET, but sensitivity may be restored by treatment with mTOR inhibitors (26,27). However, no clinical study has demonstrated that secondary resistance to ET is associated with increased PI3K signaling in patients, and synergy between ET and everolimus has not been demonstrated in patient's tumors.…”

Section: Discussionmentioning

confidence: 99%

Acquired Resistance to Endocrine Treatments Is Associated with Tumor-Specific Molecular Changes in Patient-Derived Luminal Breast Cancer Xenografts

Cottu¹,

Bièche

Assayag³

et al. 2014

Clinical Cancer Research

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Purpose: Patients with luminal breast cancer (LBC) often become endocrine resistant over time. We investigated the molecular changes associated with acquired hormonoresistances in patient-derived xenografts of LBC. Experimental Design: Two LBC xenografts (HBCx22 and HBCx34) were treated with different endocrine treatments (ET) to obtain xenografts with acquired resistances to tamoxifen (TamR) and ovariectomy (OvaR). PI3K pathway activation was analyzed by Western blot analysis and IHC and responses to ET combined to everolimus were investigated in vivo. Gene expression analyses were performed by RT-PCR and Affymetrix arrays. Results: HBCx22 TamR xenograft was cross-resistant to several hormonotherapies, whereas HBCx22 OvaR and HBCx34 TamR exhibited a treatment-specific resistance profile. PI3K pathway was similarly activated in parental and resistant xenografts but the addition of everolimus did not restore the response to tamoxifen in TamR xenografts. In contrast, the combination of fulvestrant and everolimus induced tumor regression in vivo in HBCx34 TamR, where we found a cross-talk between the estrogen receptor (ER) and PI3K pathways. Expression of several ER-controlled genes and ER coregulators was significantly changed in both TamR and OvaR tumors, indicating impaired ER transcriptional activity. Expression changes associated with hormonoresistance were both tumor and treatment specific and were enriched for genes involved in cell growth, cell death, and cell survival. Conclusions: PDX models of LBC with acquired resistance to endocrine therapies show a great diversity of resistance phenotype, associated with specific deregulations of ER-mediated gene transcription. These models offer a tool for developing anticancer therapies and to investigate the dynamics of resistance emerging during pharmacologic interventions. Clin Cancer Res; 20(16); 4314–25. ©2014 AACR.

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“…The changes in the expression of Ki-67 (proliferation-related Ki-67 antigen), phospho-S6 (phosphorylated S6 ribosomal protein), cyclin D1, and progesterone receptor signatures in breast cancer tissues were shown to be useful pharmacodynamic biomarkers that associated with fewer events in estrogen receptor-positive patients by combining everolimus with letrozole as compared to everolimus alone (56). These results suggested that the PI3K/Akt/mTOR pathway plays a key role in patients' response to anti-endocrine therapy (56)(57)(58). These examples demonstrate potential applications of using gene transcript signatures to support our molecular level understanding and prediction of clinical responses.…”

Section: Transition To Early Clinical Developmentmentioning

confidence: 99%

Strategic Applications of Gene Expression: From Drug Discovery/Development to Bedside

Bai

Alekseyenko

Statnikov

et al. 2013

AAPS J

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ABSTRACT. Gene expression is useful for identifying the molecular signature of a disease and for correlating a pharmacodynamic marker with the dose-dependent cellular responses to exposure of a drug. Gene expression offers utility to guide drug discovery by illustrating engagement of the desired cellular pathways/networks, as well as avoidance of acting on the toxicological pathways. Successful employment of gene-expression signatures in the later stages of drug development depends on their linkage to clinically meaningful phenotypic characteristics and requires a biologically meaningful mechanism combined with a stringent statistical rigor. Much of the success in clinical drug development is hinged on predefining the signature genes for their fitness for purposes of application. Specific examples are highlighted to illustrate the breadth and depth of the potential utility of gene-expression signatures in drug discovery and clinical development to targeted therapeutics at the bedside.

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Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling

Cited by 158 publications

References 19 publications

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

Acquired Resistance to Endocrine Treatments Is Associated with Tumor-Specific Molecular Changes in Patient-Derived Luminal Breast Cancer Xenografts

Strategic Applications of Gene Expression: From Drug Discovery/Development to Bedside

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