PI3K inhibition to overcome endocrine resistance in breast cancer

Keegan, Niamh M.; Gleeson, Jack Patrick; Hennessy, Bryan T.; Morris, Patrick G.

doi:10.1080/13543784.2018.1417384

Cited by 38 publications

(28 citation statements)

References 103 publications

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“…Journal of Oncology are currently PI3K inhibitors, which are being implemented in clinical trials [44,45]. Mutations in PTEN also result in important alterations in cell signalling in patients with breast cancer.…”

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confidence: 99%

Signal Transduction Pathways in Breast Cancer: The Important Role of PI3K/Akt/mTOR

Ortega

Fraile-Martínez

Asúnsolo

et al. 2020

Journal of Oncology

152

100

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Breast cancer is the cancer with the highest prevalence in women and is the number-one cause of cancer mortality worldwide. Cell transduction is a fundamental process in the development and progression of cancer. Modifications in various cell signalling pathways promote tumour cell proliferation, progression, and survival. The PI3K/Akt/mTOR pathway is an example of that, and it is involved in growth, proliferation, survival, motility, metabolism, and immune response regulation. Activation of this pathway is one of the main causes of cancer cell resistance to antitumour therapies. This makes PI3K/Akt/mTOR signalling a crucial object of study for understanding the development and progression of this disease. Thus, this pathway may have a role as a potential therapeutic target, as well as prognostic and diagnostic value, in patients with breast cancer. Despite the existence of selective PI3K/Akt/mTOR pathway inhibitors and current clinical trials, the cellular mechanisms are not yet known. The present review aims to understand the current state of this important disease and the paths that must be forged.

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mentioning

confidence: 99%

Signal Transduction Pathways in Breast Cancer: The Important Role of PI3K/Akt/mTOR

Ortega

Fraile-Martínez

Asúnsolo

et al. 2020

Journal of Oncology

152

100

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“…With the ER-positive nature of the majority of PIK3CA-mutant tumors, it may be stipulated that these cells can survive through both pathways governing proliferation and survival (18). The proof of the cooperation of the ER and PI3K pathways in the advancement of tumors arose from a clinical study (19,20). A remarkable improvement was observed in the progressive defense of ER-positive breast tumor patients who underwent with everolimus treatment, an mTOR inhibitor, combined with exemestane, an inhibitor for the anti-estrogen aromatase (21,22).…”

Section: Introductionmentioning

confidence: 99%

Alpelisib Inhibits PIK3CA-Mutant Breast Cancer Growth Through AKT-Dependent Bim Induction and Mcl-1 Degradation

Tan¹,

Zhang²,

Liu³

et al. 2020

Preprint

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Abstract Background: PIK3CA mutations are common genomic alterations in estrogen receptor (ER)-positive breast cancers, currently, the development of selective PI3Kα (phosphatidylinositol 3-kinase α) inhibitors is ongoing. The mechanisms contributing to the anticancer activity of alpelisib in PIK3CA-mutant breast cancer cells and the mechanism of acquired resistance to alpelisib remain elusive. Methods: Drug-sensitive cell lines were exposed to alpelisib to establish alpelisib-resistant cell lines. Western blotting was used to assess changes in protein expression. Apoptosis was evaluated by ﬂow cytometry. In vivo with mouse xenograft models and in vitro colony formation and MTS and assay were carried out to determine the growth inhibitory effects of the tested drugs. Protein half-lives were examined and proteasome inhibitors were used to estimate protein degradation. Gene knockdown was carried out using shRNA or siRNA. Results: In the present study, we report the potent induction of apoptosis by alpelisib in PIK3CA-mutant breast cancer cell lines. AKT phosphorylation suppression, AKT/Foxo3a-dependent Bim induction, and AKT/GSK-3β-dependent Mcl-1 degradation were observed. Apoptosis induced by alpelisib was attenuated by Mcl-1 (4A) overexpression or Bim suppression. Furthermore, alpelisib could not modulate Mcl-1 or Bim levels in cell lines that were resistant to alpelisib. AKT inhibitor and alpelisib combination restored the sensitivity of alpelisib-resistant cells to growth inhibition and apoptosis in vitro and in vivo. Conclusions: Therefore, modulation of Mcl-1 degradation and AKT-dependent Bim induction are crucial for mediating the resistance and sensitivity of PIK3CA-mutant breast tumor cells to alpelisib, thus making it a productive strategy for overcoming acquired resistance to alpelisib.

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“…Breast cancer is most predominant and second most common cause of cancer death in women (Dey et al, 2017). Hyperactivation of the phosphoinositide 3-kinase (PI3K) pathway has been associated with breast cancer tumorigenesis, drug resistance, and clinical outcome (Keegan et al, 2018;Nur Husna et al, 2018). Thus a series of PI3K inhibitors have been synthesized to test their anti-tumor activities against breast cancer (Costa et al, 2018;McRee et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Suppression of epidermal growth factor receptor‐mediated β‐catenin nuclear accumulation enhances the anti‐tumor activity of phosphoinositide 3‐kinase inhibitor in breast cancer

Niu

Wang

Liang

et al. 2019

Cell Biology International

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Phosphoinositide 3‐kinase (PI3K) signaling is frequently deregulated in breast cancer and plays a critical role in tumor progression. However, resistance to PI3K inhibitors in breast cancer has emerged, which is due to the enhanced β‐catenin nuclear accumulation. Until now, the mechanisms underlying PI3K inhibition‐induced β‐catenin nuclear accumulation remains largely unknown. In the present study, we found inhibition of PI3K with LY294002 promoted β‐catenin nuclear accumulation in MCF‐7 and MDA‐MB‐231 breast cancer cells. Combining PI3K inhibitor LY294002 with XAV‐939, an inhibitor against β‐catenin nuclear accumulation, produced an additive anti‐proliferation effect against breast cancer cells. Subsequent experiments suggested β‐catenin nuclear accumulation induced by PI3K inhibition depended on the feedback activation of epidermal growth factor receptor (EGFR) signaling pathway in breast cancer cells. Inhibition of EGFR phosphorylation with Gefitinib enhanced anti‐proliferation effect of PI3K inhibitor LY294002 in MCF‐7 and MDA‐MB‐231 cells. Taken together, our findings may elucidate a possible mechanism explaining the poor outcome of PI3K inhibitors in breast cancer treatment.

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PI3K inhibition to overcome endocrine resistance in breast cancer

Cited by 38 publications

References 103 publications

Signal Transduction Pathways in Breast Cancer: The Important Role of PI3K/Akt/mTOR

Signal Transduction Pathways in Breast Cancer: The Important Role of PI3K/Akt/mTOR

Alpelisib Inhibits PIK3CA-Mutant Breast Cancer Growth Through AKT-Dependent Bim Induction and Mcl-1 Degradation

Suppression of epidermal growth factor receptor‐mediated β‐catenin nuclear accumulation enhances the anti‐tumor activity of phosphoinositide 3‐kinase inhibitor in breast cancer

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