Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer

Donnella, Hayley; Webber, James T.; Levin, Rebecca S.; Camarda, Roman; Momčilović, Olga; Bayani, Nora; Shah, Khyati N.; Korkola, James E.; Shokat, Kevan M.; Goga, Andrei; Gordan, John D.; Bandyopadhyay, Sourav

doi:10.1038/s41589-018-0081-9

Cited by 72 publications

(68 citation statements)

References 60 publications

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“…Thus, PI3K appeared as the most promising target to sensitize the MCF-7 cells in the present approach. Although inhibition of PI3K is considered in its potency as target for several aspects in oncology, cells react differently and dynamically to inhibitory approaches and can drive resistance or tumorigenicity via rewiring of signaling pathways [51]. An active crosstalk of the PI3K/AKT pathway with MAPK signaling route is known [52] and becomes also evident by our findings.…”

Section: Discussionsupporting

confidence: 63%

Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization

Jakubzig

Baltes

Henze

et al. 2018

Cancers

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Tumor cell binding to microenvironment components such as collagen type 1 (COL1) attenuates the sensitivity to cytotoxic drugs like cisplatin (CDDP) or mitoxantrone (MX), referred to as cell adhesion mediated drug resistance (CAM-DR). CAM-DR is considered as the onset for resistance mutations, but underlying mechanisms remain elusive. To evaluate CAM-DR as target for sensitization strategies, we analyzed signaling pathways in human estrogen-positive MCF-7 and triple-negative MDA-MB-231 breast cancer cells by western blot, proteome profiler array and TOP-flash assay in presence of COL1. β1-Integrins, known to bind COL1, appear as key for mediating COL1-related resistance in both cell lines that primarily follows FAK/PI3K/AKT pathway in MCF-7, and MAPK pathway in MDA-MB-231 cells. Notably, pCREB is highly elevated in both cell lines. Consequently, blocking these pathways sensitizes the cells evidently to CDDP and MX treatment. Wnt signaling is not relevant in this context. A β1-integrin knockdown of MCF-7 cells (MCF-7-β1-kd) reveals a signaling shift from FAK/PI3K/AKT to MAPK pathway, thus CREB emerges as a promising primary target for sensitization in MDA-MB-231, and secondary target in MCF-7 cells. Concluding, we provide evidence for importance of CAM-DR in breast cancer cells and identify intracellular signaling pathways as targets to sensitize cells for cytotoxicity treatment regimes.

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Section: Discussionsupporting

confidence: 63%

Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization

Jakubzig

Baltes

Henze

et al. 2018

Cancers

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“…In order to optimize the efficacy and selectivity of oxostephanine against cancer cells, a combinatorial approach could be employed based on what has been found for other Aurora kinase inhibitors. For example, the inhibition of Aurora A in combination with the PI3Kα inhibitor BYL719, enhances apoptosis in breast cancer models [44]. Taken together, our data suggests that oxostephanine (1) provides a lead structure that could be optimized as a novel therapeutic in breast cancer and potentially other cancers.…”

Section: Oxostephanine Inhibits Aurora Kinase Activity In Vitro and Imentioning

confidence: 68%

Cytotoxic and Anti-Plasmodial Activities of Stephania dielsiana Y.C. Wu Extracts and the Isolated Compounds

et al. 2020

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Natural products remain a viable source of novel therapeutics, and as detection and extraction techniques improve, we can identify more molecules from a broader set of plant tissues. The aim of this study was an investigation of the cytotoxic and anti-plasmodial activities of the methanol extract from Stephania dielsiana Y.C. Wu leaves and its isolated compounds. Our study led to the isolation of seven alkaloids, among which oxostephanine (1) is the most active against several cancer cell lines including HeLa, MDA-MB231, MDA-MB-468, MCF-7, and non-cancer cell lines, such as 184B5 and MCF10A, with IC50 values ranging from 1.66 to 4.35 μM. Morever, oxostephanine (1) is on average two-fold more active against cancer cells than stephanine (3), having a similar chemical structure. Cells treated with oxostephanine (1) are arrested at G2/M cell cycle, followed by the formation of aneuploidy and apoptotic cell death. The G2/M arrest appears to be due, at least in part, to the inactivation of Aurora kinases, which is implicated in the onset and progression of many forms of human cancer. An in-silico molecular modeling study suggests that oxostephanine (1) binds to the ATP binding pocket of Aurora kinases to inactivate their activities. Unlike oxostephanine (1), thailandine (2) is highly effective against only the triple-negative MDA-MB-468 breast cancer cells. However, it showed excellent selectivity against the cancer cell line when compared to its effects on non-cancer cells. Furthermore, thailandine (2) showed excellent anti-plasmodial activity against both chloroquine-susceptible 3D7 and chloroquine-resistant W2 Plasmodium falciparum strains. The structure–activity relationship of isolated compound was also discussed in this study. The results of this study support the traditional use of Stephania dielsiana Y.C. Wu and the lead molecules identified can be further optimized for the development of highly effective and safe anti-cancer and anti-plasmodial drugs.

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“…The sensitivity to mTOR inhibitors is regulated by other oncogenic pathways, such as PI3K, MAPK, AURKA, and NF-kB signaling [164, 165]. Both the Ras/MAPK and PI3K/Akt/mTOR pathways are tightly involved in tumorigenesis.…”

Section: Principle Mechanisms Of Mtor Inhibitor Resistance In Cancermentioning

confidence: 99%

Targeting mTOR for cancer therapy

et al. 2019

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Mechanistic target of rapamycin (mTOR) is a protein kinase regulating cell growth, survival, metabolism, and immunity. mTOR is usually assembled into several complexes such as mTOR complex 1/2 (mTORC1/2). In cooperation with raptor, rictor, LST8, and mSin1, key components in mTORC1 or mTORC2, mTOR catalyzes the phosphorylation of multiple targets such as ribosomal protein S6 kinase β-1 (S6K1), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), Akt, protein kinase C (PKC), and type-I insulin-like growth factor receptor (IGF-IR), thereby regulating protein synthesis, nutrients metabolism, growth factor signaling, cell growth, and migration. Activation of mTOR promotes tumor growth and metastasis. Many mTOR inhibitors have been developed to treat cancer. While some of the mTOR inhibitors have been approved to treat human cancer, more mTOR inhibitors are being evaluated in clinical trials. Here, we update recent advances in exploring mTOR signaling and the development of mTOR inhibitors for cancer therapy. In addition, we discuss the mechanisms underlying the resistance to mTOR inhibitors in cancer cells.

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Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer

Cited by 72 publications

References 60 publications

Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization

Mechanisms of Matrix-Induced Chemoresistance of Breast Cancer Cells—Deciphering Novel Potential Targets for a Cell Sensitization

Cytotoxic and Anti-Plasmodial Activities of Stephania dielsiana Y.C. Wu Extracts and the Isolated Compounds

Targeting mTOR for cancer therapy

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