Dual treatments targeting IGF-1R, PI3K, mTORC or MEK synergize to inhibit cell growth, induce apoptosis, and arrest cell cycle at G1 phase in MDA-MB-231 cell line

Ayub, Ayunadirah; Yip, Wai Kien; Seow, Heng Fong

doi:10.1016/j.biopha.2015.08.031

Cited by 34 publications

(28 citation statements)

References 34 publications

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“…5B,C). Inhibition of mTORC1 and mTORC2 by KU0063794 is known to block the cell cycle, cell growth and cell survival (Zhang et al, 2013;Ayub et al, 2015). Consistent with this notion, endothelial cell colonies that were formed in the presence of KU0063794 were smaller than the colonies observed in the control cultures (Fig.…”

Section: Dual Inhibition Of Mtorc1 and Mtorc2 Fails To Induce Elongatsupporting

confidence: 72%

Inhibition of the PI3K–Akt and mTORC1 signaling pathways promotes the elongation of vascular endothelial cells

Tsuji‐Tamura

Ogawa

2016

Journal of Cell Science

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Endothelial cell morphology needs to be properly regulated during angiogenesis. Vascular endothelial growth factor (VEGF) induces endothelial cell elongation, which promotes sprouting of pre-existing vessels. However, therapeutic angiogenesis using VEGF has been hampered by side effects such as elevated vascular permeability. Here, we attempted to induce endothelial cell elongation without an overdose of VEGF. By screening a library of chemical inhibitors, we identified phosphatidylinositol 3-kinase (PI3K)-Akt pathway inhibitors and mammalian target of rapamycin complex 1 (mTORC1) inhibitors as potent inducers of endothelial cell elongation. The elongation required VEGF at a low concentration, which was insufficient to elicit the same effect by itself. The elongation also depended on Foxo1, a transcription factor indispensable for angiogenesis. Interestingly, the Foxo1 dependency of the elongation was overridden by inhibition of mTORC1, but not by PI3K-Akt, under stimulation by a high concentration of VEGF. Dual inhibition of mTORC1 and mTORC2 failed to induce cell elongation, revealing mTORC2 as a positive regulator of elongation. Our findings suggest that the PI3K-AktFoxo1 and mTORC1-mTORC2 pathways differentially regulate endothelial cell elongation, depending on the microenvironmental levels of VEGF.

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Section: Dual Inhibition Of Mtorc1 and Mtorc2 Fails To Induce Elongatsupporting

confidence: 72%

Inhibition of the PI3K–Akt and mTORC1 signaling pathways promotes the elongation of vascular endothelial cells

Tsuji‐Tamura

Ogawa

2016

Journal of Cell Science

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“…The Ras-MEK-ERK pathway, as an important contributor to cell proliferation and growth, is a likely candidate for codependence in cases of PI3K inhibitor resistance. Previous studies have demonstrated that PI3K and MEK inhibitors are synergistic in some HNSCCs 13-15 , as well as in a variety of other cancer types 16-19 . In addition, based on preclinical evidence and frequent genetic alterations in HNSCC, trials for pan PI3K inhibitor BKM120 and alpha-isoform specific PI3K inhibitor BYL719 are ongoing (examples include: NCT02537223, NCT02051751 and NCT01602315).…”

Section: Introductionmentioning

confidence: 99%

Differential compensation mechanisms define resistance to PI3K inhibitors in PIK3CA amplified HNSCC

Michmerhuizen

Leonard

Kulkarni

et al. 2016

Otorhinolaryngol Head Neck Surg

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Objective Recent sequencing studies of head and neck squamous cell carcinomas (HNSCCs) have identified the phosphatidylinositol 3-kinase (PI3K) pathway as the most frequently mutated, oncogenic pathway in this cancer type. Despite the frequency of activating genomic alterations in PIK3CA (the gene encoding the catalytic subunit of PI3K, targeted inhibitors of PI3K have not shown clinical efficacy as monotherapies. We hypothesized that co-dependent pathways, including the Ras-MEK-ERK pathway, may still be functional in the presence of PI3K inhibitors and might serve as mediators of this resistance. Methods We assessed the hypothesis using resazurin cell viability and trypan blue exclusion assays. We also used Western blot to characterize Ras-MEK-ERK pathway activity. Study Design We evaluated this hypothesis in six PIK3CA-amplified, PI3K inhibitor-resistant HNSCC cell lines following treatment with pan and alpha-isoform selective PI3K inhibitors (BKM120 and HS-173 respectively). We also tested the effect of combination treatment with PI3K inhibitor HS-173 and MEK inhibitor trametinib or EGFR inhibitor gefitinib. Results Our results displayed maintenance of Ras-MEK-ERK pathway activity in 4 of 6 HNSCC cell lines after PI3K inhibitor treatment. We also found that UM-SCC-69 and UM-SCC-108 cells display synergistic responses to dual therapy. Conclusion This study suggests that inhibition of the PI3K and Ras-MEK-ERK pathways might be effective in some HNSCC patients; however, it also prompts the study of additional resistance mechanisms to identify synergistic combination therapies for tumors resistant to these di-therapies.

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“…A variety of combinatorial therapies targeting IGF1R (NVP-AEW541), PI3K (NVP-BKM120), mTORC (KU0063794) and MEK (PD0325901) in the MDA-MB-231 cell line have shown synergistic effects in vitro by a reduction in cell growth (i.e. combination index (CI) < 1) in parallel with an increase in cell apoptosis and G 0 /G 1 cell cycle arrest (Ayub et al 2015). Importantly, these combinations have a potential to prevent the re-activation of these tyrosine kinase pathways and reduce toxicity by the administration of lower drug doses.…”

Section: Downstream Mediators Of Igf1r Signaling: Potential Therapeutmentioning

confidence: 99%

Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

Ochnik

Baxter

2016

Endocrine-Related Cancer

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Insulin-like growth factor receptor (IGF1R) signaling as a therapeutic target has been widely studied and clinically tested. Despite the vast amount of literature supporting the biological role of IGF1R in breast cancer, effective clinical translation in targeting its activity as a cancer therapy has not been successful. The intrinsic complexity of cancer cell signaling mediated by many tyrosine kinase growth factor receptors that work together to modulate each other and intracellular downstream mediators in the cell highlights that studying IGF1R expression and activity as a prognostic factor and therapeutic target in isolation is certainly associated with problems. This review discusses the current literature and clinical trials associated with IGF-1 signaling and attempts to look at new ways of designing novel IGF1R-directed breast cancer therapy approaches to target its activity and/or intracellular downstream signaling pathways in IGF1R-expressing breast cancers. 23:11 Review A M Ochnik and R C BaxterDual IGF-directed breast cancer therapies

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Dual treatments targeting IGF-1R, PI3K, mTORC or MEK synergize to inhibit cell growth, induce apoptosis, and arrest cell cycle at G1 phase in MDA-MB-231 cell line

Cited by 34 publications

References 34 publications

Inhibition of the PI3K–Akt and mTORC1 signaling pathways promotes the elongation of vascular endothelial cells

Inhibition of the PI3K–Akt and mTORC1 signaling pathways promotes the elongation of vascular endothelial cells

Differential compensation mechanisms define resistance to PI3K inhibitors in PIK3CA amplified HNSCC

Combination therapy approaches to target insulin-like growth factor receptor signaling in breast cancer

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