AKT2 is frequently upregulated in HER-2/neu-positive breast cancers and may contribute to tumor aggressiveness by enhancing cell survival

Bacus, Sarah; Altomare, Deborah A.; Lyass, Ljuba; Chin, Dot; Farrell, Michael; Gurova, Katerina V.; Gudkov, Andrei V.; Testa, Joseph R.

doi:10.1038/sj.onc.1205438

Cited by 129 publications

(104 citation statements)

References 49 publications

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“…90 LY294002 and wortmannin (both inhibitors of PI-3K) can decrease apoptosis-resistance of cells with overactivated receptor RTK. 91 ZD1839 is a quinazolone that inhibits the EGF receptor with an IC50 of 0.02 µM and increases the antitumor effects of chemotherapy and radiation therapy. 92 …”

Section: Inhibition Of Mitogen-activated Signaling Sensitized Cancer mentioning

confidence: 99%

Cyclotherapy: Protection of Normal Cells and Unshielding of Cancer Cells

Blagosklonny¹,

Darżynkiewicz²

2002

Cell Cycle

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Avoidance of apoptosis and mitogen-independent growth are hallmarks of cancer. Mitogen-activated kinases (for example, ErbB1, Raf-1, MEK, PI-3-K, mTOR) can suppress chemotherapy-induced apoptosis in cancer cells. While kinase inhibitors restore susceptibility of cancer cells to apoptosis, they do not necessarily cause growth arrest in cancer cells harboring additional mutations in downstream signaling pathways such as inactivation of Rb and overexpression of c-myc. This article provides a conceptual basis for a novel use of inhibitors of mitogenic kinases. While arresting growth of normal cells, kinase inhibitors may not arrest cancer cells but instead can sensitize them to apoptosis. Following pretreatment with low doses of kinase inhibitors, the chemotherapy that predominantly induces apoptosis in cycling cells (cyclotherapy) will kill cancer cells while sparing normal cells.

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Section: Inhibition Of Mitogen-activated Signaling Sensitized Cancer mentioning

confidence: 99%

Cyclotherapy: Protection of Normal Cells and Unshielding of Cancer Cells

Blagosklonny¹,

Darżynkiewicz²

2002

Cell Cycle

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“…Certain SH2 and phosphotyrosine-binding-domain proteins preferentially associate with specific ErbB receptors. For example, ErbB3 contains multiple cytoplasmic docking sites for the p85 subunit of phosphatidylinositol 3-kinase (PI3K), a prosurvival factor involved in resistance to hormonal/chemotherapy (Cheng et al, 1992;Prigent and Gullick, 1994;Soltoff et al, 1994;Bacus et al, 2002;Vivanco and Sawyers, 2002;Yakes et al, 2002). Accordingly, ErbB3-containing heterodimers, specifically ErbB2-ErbB3 complexes, elicit potent mitogenic and prosurvival signals (Alimandi et al, 1995;Siegel et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016

et al. 2004

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The expression of the NH 2 terminally truncated ErbB2 receptor (p95 ErbB2 ) in breast cancer correlates with metastatic disease progression compared with the expression of full-length p185 ErbB2 . We now show that heregulin (HRG), but not EGF, stimulates p95 ErbB2 phosphorylation in BT474 breast cancer cells. Furthermore, phosphop95 ErbB2 forms heterodimers with ErbB3, but not EGFR, while p185 ErbB2 heterodimerizes with both EGFR and ErbB3. The predilection of p95 ErbB2 to heterodimerize with ErbB3 provides an explanation for its regulation by HRG, an ErbB3 ligand. GW572016, a reversible small molecule inhibitor of EGFR and ErbB2 tyrosine kinases, inhibits baseline p95 ErbB2 phosphorylation in BT474 cells and tumor xenografts. Inhibition of p95 ErbB2 , p185 ErbB2 , and EGFR phosphorylation by GW572016 resulted in the inhibition of downstream phospho-Erk1/2, phospho-AKT, and cyclin D steady-state protein levels. Increased phosphorylation of p95 ErbB2 and AKT in response to HRG was abrogated to varying degrees by GW572016. In contrast, trastuzumab did not inhibit p95 ErbB2 phosphorylation or the expression of downstream phospho-Erk1/2, phospho-AKT, or cyclin D. It is tempting to speculate that trastuzumab resistance may be mediated in part by the selection of p95 ErbB2 -expressing breast cancer cells capable of exerting potent growth and prosurvival signals through p95 ErbB2 -ErbB3 heterodimers. Thus, p95 ErbB2 represents a target for therapeutic intervention, and one that is sensitive to GW572016 therapy.

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“…Cancer cells commonly have mutations and/or overexpression of several signalling molecules, resulting in the activation of mTOR and its substrates S6K1 and 4E-BP1. For example, the HER2 overexpression observed in about one-third of breast cancers is associated with activation of PI3-kinase/Akt/mTOR signalling (Bacus et al, 2002;Zhou et al, 2004), resistance to stress-induced apoptosis (Bacus et al, 2002), and tumour aggressiveness (Cobleigh et al, 1999;Zhou et al, 2004). Activation of the PI3-kinase/Akt/ mTOR signalling pathway may be inhibited by rapamycin, which blocks mTOR activation, resulting in the inhibition of tumour growth (see reviews by Faivre et al, 2006;Georgakis and Younes, 2006).…”

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confidence: 99%

Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours

et al. 2009

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Everolimus displays antiproliferative effects on cancer cells, yields antiangiogenic activity in established tumours, and shows synergistic activity with paclitaxel in preclinical models. This study assessed the safety and the pharmacokinetic interactions of everolimus and paclitaxel in patients with advanced malignancies. Everolimus was dose escalated from 15 to 30 mg and administered with paclitaxel 80 mg m À2 on days 1, 8, and 15 every 28 days. Safety was assessed weekly, and dose-limiting toxicity (DLT) was evaluated in cycle 1. A total of 16 patients (median age 54.5 years, range 33 -69) were entered; 11 had prior taxane therapy for breast (n ¼ 5), ovarian (n ¼ 3), and vaginal cancer (n ¼ 1) or angiosarcoma (n ¼ 2). Grade 3 neutropenia in six patients met the criteria for DLT in two patients receiving everolimus 30 mg weekly. Other drug-related grade 3 toxicities were leucopenia, anaemia, thrombocytopenia, stomatitis, asthenia, and increased liver enzymes. Tumour stabilisation reported in 11 patients exceeded 6 months in 2 patients with breast cancer. Everolimus showed an acceptable safety profile at the dose of 30 mg when combined with weekly paclitaxel 80 mg m À2 , warranting further clinical investigation.

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AKT2 is frequently upregulated in HER-2/neu-positive breast cancers and may contribute to tumor aggressiveness by enhancing cell survival

Cited by 129 publications

References 49 publications

Cyclotherapy: Protection of Normal Cells and Unshielding of Cancer Cells

Cyclotherapy: Protection of Normal Cells and Unshielding of Cancer Cells

Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016

Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours

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