Phosphorylation of Akt (Ser473) Predicts Poor Clinical Outcome in Oropharyngeal Squamous Cell Cancer

Yang, Ziwei; Weinberger, Paul M.; Sasaki, Clarence T.; Egleston, Brian L.; Speier, William; Haffty, Bruce G.; Kowalski, Diane; Camp, Robert L.; Rimm, David L.; Vairaktaris, Eleftherios; Burtness, Barbara; Psyrri, Amanda

doi:10.1158/1055-9965.epi-06-0121

Cited by 71 publications

(52 citation statements)

References 25 publications

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“…Either of these mechanisms can lead to rebound enhancement of AKT function and induce a recovery of prosurvival signals (Figure 10). High AKT activity is associated with a poor prognosis as well as resistance to chemotherapy (35,36).…”

Section: Figurementioning

confidence: 99%

Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells

Kharas¹,

Janes²,

Scarfone³

et al. 2008

J. Clin. Invest.

138

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Some cases of pre-B cell acute lymphoblastic leukemia (pre-B-ALL) are caused by the Philadelphia (Ph) chromosome-encoded BCR-ABL oncogene, and these tend to have a poor prognosis. Inhibitors of the PI3K/AKT pathway reduce BCR-ABL-mediated transformation in vitro; however, the specific PI3K isoforms involved are poorly defined. Using a murine model of Ph + pre-B-ALL, we found that deletion of both Pik3r1 and Pik3r2, genes encoding class IA PI3K regulatory isoforms, severely impaired transformation. BCR-ABL-dependent pre/pro-B cell lines could be established at low frequency from progenitors that lacked these genes, but the cells were smaller, proliferated more slowly, and failed to cause leukemia in vivo. These cell lines displayed nearly undetectable PI3K signaling function and were resistant to the PI3K inhibitor wortmannin. However, they maintained activation of mammalian target of rapamycin (mTOR) and were more sensitive to rapamycin. Treatment with rapamycin caused feedback activation of AKT in WT cell lines but not PI3K-deficient lines. A dual inhibitor of PI3K and mTOR, PI-103, was more effective than rapamycin at suppressing proliferation of mouse pre-B-ALL and human CD19 + CD34 + Ph + ALL leukemia cells treated with the ABL kinase inhibitor imatinib. Our findings provide mechanistic insights into PI3K dependency in oncogenic networks and provide a rationale for targeting class IA PI3K, alone or together with mTOR, in the treatment of Ph + ALL.

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Section: Figurementioning

confidence: 99%

Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells

Kharas¹,

Janes²,

Scarfone³

et al. 2008

J. Clin. Invest.

138

View full text Add to dashboard Cite

show abstract

“…Interestingly, TGF-b polymorphisms have been reported to be a susceptibility marker for HPV16 status amongst patients with OPC (35). Furthermore, the miR106b-25 cluster can also target PTEN (20), which in turn will activate AKT, which correlates with adverse outcome for patients with OPC (36). Hence, dysregulation of MCM7 and the miR-106b-25 cluster could lead to OPC development via aberrant TGF-b and PTEN signaling (Fig.…”

Section: Discussionmentioning

confidence: 99%

Potentially Prognostic miRNAs in HPV-Associated Oropharyngeal Carcinoma

Hui

Lin

et al. 2013

Clinical Cancer Research

105

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Purpose: Deregulation of miRNAs is associated with almost all human malignancies. Human papillomavirus (HPV)-associated oropharyngeal carcinoma (OPC) has a significantly more favorable outcome compared with HPV-negative OPCs; however, the underlying mechanisms are not well understood. Hence, the objectives of this study were to determine whether miRNA expression differed as a function of HPV status and to assess whether such miRNAs provide prognostic value beyond HPV status.Methods: Global miRNA profilings were conducted on 88 formalin-fixed and paraffin-embedded (FFPE) OPC biopsies (p16-positive: 56; p16-negative: 32), wherein the expression levels of 365 miRNAs plus 3 endogenous controls were simultaneously measured using quantitative real-time (qRT)-PCR. Seven FFPE specimens of histologically normal tonsils were used as controls.Results: Overall, 224 miRNAs were expressed in more than 80% of the investigated samples, with 128 (57%) being significantly differentially expressed between tumor versus normal tissues (P < 0.05). Upregulated miR-20b, miR-9, and miR-9 Ã were significantly associated with HPV/p16-status. Three miRNA sets were significantly associated with overall survival (miR-107, miR-151, miR-492; P ¼ 0.0002), diseasefree survival (miR-20b, miR-107, miR-151, miR-182, miR-361; P ¼ 0.0001), and distant metastasis (miR-151, miR-152, miR-324-5p, miR-361, miR492; P ¼ 0.0087), which retained significance even after adjusting for p16 status. The associated biologic functions of these miRNAs include immune surveillance, treatment resistance, invasion, and metastasis. Conclusion: We have identified several miRNAs, which associate with HPV status in OPC; furthermore, three candidate prognostic sets of miRNAs seem to correlate with clinical outcome, independent of p16 status. Furthermore, evaluations will offer biologic insights into the mechanisms underlying the differences between HPV-positive versus HPV-negative OPC.

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“…Massarelli et al reported that tongue cancer patients with Ki67 expression showed significantly shorter disease-free survival [8]. Yu et al reported that OPSCC patients with a low Ki67 level had a lower 5-year local recurrence rate and better 5-year overall survival rate [9].…”

Section: Discussionmentioning

confidence: 99%

Differences in Expression of EGFR, Ki67 and p-EPK in Oral Cavity Squamous Cell Carcinoma

Bu¹,

Bu²,

Chen³

et al. 2016

Trop. J. Pharm Res

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Phosphorylation of Akt (Ser473) Predicts Poor Clinical Outcome in Oropharyngeal Squamous Cell Cancer

Cited by 71 publications

References 25 publications

Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells

Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells

Potentially Prognostic miRNAs in HPV-Associated Oropharyngeal Carcinoma

Differences in Expression of EGFR, Ki67 and p-EPK in Oral Cavity Squamous Cell Carcinoma

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