Comparison of the effects of the PI3K/mTOR inhibitors NVP-BEZ235 and GSK2126458 on tamoxifen-resistant breast cancer cells

Leung, Euphemia; Kim, Ji Eun; Rewcastle, Gordon W.; Finlay, Graeme J.; Baguley, Bruce C.

doi:10.4161/cbt.11.11.15527

Cited by 68 publications

(65 citation statements)

References 31 publications

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“…Besides, LY294002, a PI3K inhibitor, also showed synergistic antitumor efficacy with tamoxifen treatment, which suggested that ER-positive breast cancer tumors may restore sensitivity of endocrine therapy by concurrent treatment with PI3K/AKT/mTOR signaling pathway inhibitors. Both everolimus and LY294002 acted mainly by induction of cell-cycle arrest, particularly in G 1 phase, which was similar with other study using PI3K and mTOR dual inhibitors (17). Target mTOR therapy alone can cause a multiple feedback loops and cross-talk with other signaling pathways, which may lead to pAkt activation and attenuate the responses to mTOR inhibition (14).…”

Section: Discussionsupporting

confidence: 72%

See 1 more Smart Citation

Dual Inhibition of PI3K and mTOR Mitigates Compensatory AKT Activation and Improves Tamoxifen Response in Breast Cancer

Chen

Zhao

Hao

et al. 2013

Molecular Cancer Research

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Everolimus, an mTOR inhibitor, showed great clinical efficacy in combination with tamoxifen, letrozole, or exemestane for the treatment of estrogen receptor-positive (ER+) breast cancer. However, its antitumor activity was shown to be compromised by a compensatory process involving AKT activation. Here, it was determined whether combining an additional PI3K inhibitor can reverse this phenomenon and improve treatment efficacy. In breast cancer cells

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Section: Discussionsupporting

confidence: 72%

“…BEZ235, a dual PI3K and mTOR inhibitor, has been shown to be able to inhibit the growth of breast cancer cell with PI3K mutations (16). Thus, novel PI3K inhibitors in combination with mTOR antagonists might be a better treatment regimen in ER-positive breast cancer (17).…”

Section: Introductionmentioning

confidence: 99%

Dual Inhibition of PI3K and mTOR Mitigates Compensatory AKT Activation and Improves Tamoxifen Response in Breast Cancer

Chen

Zhao

Hao

et al. 2013

Molecular Cancer Research

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“…This will allow therapies to be made swiftly available for all suitable candidates. We can only hope that novel and safe targeted anticancer agents will come from these drug discovery efforts [171][172][173][174][175][176][177][178] .…”

Section: Resultsmentioning

confidence: 99%

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

2012

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The PI3K-Akt pathway is a vital regulator of cell proliferation and survival. Alterations in the PIK3CA gene that lead to enhanced PI3K kinase activity have been reported in many human cancer types, including cancers of the colon, breast, brain, liver, stomach and lung. Deregulation of PI3K causes aberrant Akt activity. Therefore targeting this pathway could have implications for cancer treatment. The first generation PI3K-Akt inhibitors were proven to be highly effective with a low IC 50 , but later, they were shown to have toxic side effects and poor pharmacological properties and selectivity. Thus, these inhibitors were only effective in preclinical models. However, derivatives of these first generation inhibitors are much more selective and are quite effective in targeting the PI3K-Akt pathway, either alone or in combination. These second-generation inhibitors are essentially a specific chemical moiety that helps to form a strong hydrogen bond interaction with the PI3K/Akt molecule. The goal of this review is to delineate the current efforts that have been undertaken to inhibit the various components of the PI3K and Akt pathway in different types of cancer both in vitro and in vivo. Our focus here is on these novel therapies and their inhibitory effects that depend upon their chemical nature, as well as their development towards clinical trials.

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“…GSK2126458 has been identified as a highly potent, orally bioavailable inhibitor of p110a, p110b, p110g, p110d, mTORC1, and mTORC2. It can induce a significant reduction in the levels of p-Akt, inhibit growth, and induce G 1 phase arrest in breast cancer (24). Furthermore, GSK2126458 is currently tested in a phase I clinical trial in patients with solid tumors or lymphoma (NCT00972686).…”

Section: Introductionmentioning

confidence: 99%

“…GSK2126458 and PKI-587 are highly selective and potent small-molecule inhibitors which could effectively suppress both multiple class I PI3K isoforms and mTOR kinase activity (24,25). GSK2126458 has been identified as a highly potent, orally bioavailable inhibitor of p110a, p110b, p110g, p110d, mTORC1, and mTORC2.…”

Section: Introductionmentioning

confidence: 99%

Dual PI3K/mTOR Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma

Liu

Sun

et al. 2015

Molecular Cancer Therapeutics

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Although combined chemoradiotherapy has provided considerable improvements for nasopharyngeal carcinoma (NPC), recurrence and metastasis are still frequent. The PI3K/Akt/mTOR pathway plays a critical role in tumor formation and tumor cell survival after radiation-induced DNA damage. In the present study, we evaluated whether inhibition of PI3K/mTOR by two novel dual inhibitors, GSK2126458 and PKI-587, could suppress tumor progression and sensitize NPC cells to radiation. Four NPC cell lines (CNE-1, CNE-2, 5-8F, and 6-10B) were used to analyze the effects of GSK216458 and PKI-587 on cell proliferation, migration, invasion, clonogenic survival, amount of residual g-H2AX foci, cell cycle, and apoptosis after radiation. A 5-8F xenograft model was used to evaluate the in vivo effects of the two compounds in combination with ionizing radiation (IR).Both GSK216458 and PKI-587 effectively inhibited cell proliferation and motility in NPC cells and suppressed phosphorylation of Akt, mTOR, S6, and 4EBP1 proteins in a concentration-and time-dependent manner. Moreover, both compounds sensitized NPC cells to IR by increasing DNA damage, enhancing G 2 -M cellcycle delay, and inducing apoptosis. In vivo, the combination of IR with GSK2126458 or PKI-587 significantly inhibited tumor growth. Antitumor effect was correlated with induction of apoptosis and suppression of the phosphorylation of mTOR, Akt, and 4EBP1. These new findings suggest the usefulness of PI3K/mTOR dual inhibition for antitumor and radiosensitizing. The combination of IR with a dual PI3K/mTOR inhibitor, GSK2126458 or PKI-587, might be a promising therapeutic strategy for NPC. Mol Cancer Ther; 14(2); 429-39. Ó2014 AACR.

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Comparison of the effects of the PI3K/mTOR inhibitors NVP-BEZ235 and GSK2126458 on tamoxifen-resistant breast cancer cells

Cited by 68 publications

References 31 publications

Dual Inhibition of PI3K and mTOR Mitigates Compensatory AKT Activation and Improves Tamoxifen Response in Breast Cancer

Dual Inhibition of PI3K and mTOR Mitigates Compensatory AKT Activation and Improves Tamoxifen Response in Breast Cancer

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

Dual PI3K/mTOR Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma

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