Akt Phosphorylation and Gefitinib Efficacy in Patients With Advanced Non-Small-Cell Lung Cancer

Cappuzzo, Federico; Magrini, Elisabetta; Ceresoli, Giovanni Luca; Bartolini, Stefania; Rossi, Elisa; Ludovini, Vienna; Gregorc, Vanesa; Ligorio, Claudia; Cancellieri, Alessandra; Damiani, Stefania; Spreafico, Anna; Paties, Carlo; Lombardo, Laura; Calandri, Cesare; Bellezza, Guido; Tonato, Maurizio; Crinò, Lucio

doi:10.1093/jnci/djh217

Cited by 353 publications

(287 citation statements)

References 30 publications

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“…Shah et al 40 reported that p-AKT1 was strongly correlated with well-differentiated tumors, and that p-AKT1 expression in non-small cell lung cancer was a favorable independent prognostic factor. In a study by Cappuzzo et al, 41 p-AKT1 was associated with bronchioloalceolar carcinoma, which is a well-differentiated form of adenocarcinoma, and p-AKT1 positivity was associated with a reduced risk of disease progression. Taken together, there are tumors with high p-AKT1 or p-MTOR expression that remain well differentiated, seldom metastasize, and thus are associated with a better survival.…”

Section: Discussionmentioning

confidence: 98%

The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas

Lee

Choi

et al. 2012

Modern Pathology

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AKT1 signaling pathway is important for the regulation of protein synthesis and cell survival with implications in carcinogenesis. In this study, we explored the prognostic significance of AKT1 pathway in intrahepatic cholangiocarcinomas. We investigated the status of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), phosphorylated (p) AKT1 (p-AKT1), p-mammalian target of rapamycin (p-MTOR), p-p70 ribosomal protein S6 kinase (p-RPS6KB2) and p-eukaryotic initiation factor 4E-binding protein-1 (p-EIF4EBP1) in 101 intrahepatic cholangiocarcinomas by immunohistochemistry. Western blot analysis was performed to verify the expression levels of p-AKT1 and p-MTOR. The relationship of protein expression with clinicopathological data and the correlations of protein expression levels were explored. The overexpression of p-AKT1, p-MTOR, and PTEN was associated with a better survival in patients with intrahepatic cholangiocarcinoma (P ¼ 0.0137, 0.0194, and 0.0337, respectively). In a multivariate analysis, PTEN was an independent prognostic factor, and p-AKT1 showed tendency (P ¼ 0.032 and 0.051, respectively). The overexpression of p-MTOR was correlated with well-to-moderately differentiated tumors (Po0.001) and tumors without metastasis (P ¼ 0.046). Expression levels of the AKT1 signaling pathway proteins in this study showed positive correlations with each other, except for PTEN. Aberrant expressions of p-AKT1 and p-MTOR in intrahepatic cholangiocarcinoma were associated with a favorable prognosis, possibly in a PTEN-independent manner. Our results indicate that dysregulation of the AKT1 pathway may have an important role in the development of intrahepatic cholangiocarcinoma, but not necessarily in the progression of the disease.

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Section: Discussionmentioning

confidence: 98%

The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas

Lee

Choi

et al. 2012

Modern Pathology

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“…Findings in preclinical and clinical studies have highlighted the activation status of the Akt protein (Cappuzzo et al, 2004;Sordella et al, 2004).Akt, a serine/threonine kinase acts downstream of EGFR to regulate many cellular processes, including cell survival, proliferation and growth, and is activated by phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)

et al. 2007

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To investigate the role of gefitinib in patients with high-grade gliomas (HGGs), a phase II trial (1839IL/0116) was conducted in patients with disease recurrence following surgery plus radiotherapy and first-line chemotherapy. Adult patients with histologically confirmed recurrent HGGs following surgery, radiotherapy and first-line chemotherapy, were considered eligible. Patients were treated with gefitinib (250 mgday À1 ) continuously until disease progression. The primary end point was progression-free survival at 6 months progression-free survival at 6 months (PFS-6). Tissue biomarkers (epidermal growth factor receptor (EGFR) gene status and expression, phosphorylated Akt (p-Akt) expression) were assessed. Twenty-eight patients (median age, 55 years; median ECOG performance status, 1) were enrolled; all were evaluable for drug activity and safety. Sixteen patients had glioblastoma, three patients had anaplastic oligodendrogliomas and nine patients had anaplastic astrocytoma. Five patients (17.9%, 95% CI 6.1 -36.9%) showed disease stabilisation. The overall median time to progression was 8.4 (range 2 -104 þ ) weeks and PFS-6 was 14.3% (95% CI 4.0 -32.7%). The median overall survival was 24.6 weeks (range 4 -104 þ ). No grade 3 -4 gefitinib-related toxicity was found. Gefitinib showed limited activity in patients affected by HGGs. Epidermal growth factor receptor expression or gene status, and p-Akt expression do not seem to predict activity of this drug.

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“…AKT kinase is efficiently induced by growth factors like EGFR ligands or by ionizing radiation through the EGFR-mediated activation of PI3K (28)(29)(30)(31). PI3K itself is a heterodimeric complex composed of an 85-kDa regulatory subunit and a 110-kDa catalytic subunit.…”

Section: Introductionmentioning

confidence: 99%

Stimulated PI3K-AKT Signaling Mediated through Ligand or Radiation-Induced EGFR Depends Indirectly, but not Directly, on Constitutive K-Ras Activity

Toulany

Baumann

Rodemann

2007

Molecular Cancer Research

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Akt Phosphorylation and Gefitinib Efficacy in Patients With Advanced Non-Small-Cell Lung Cancer

Abstract: Patients with P-Akt-positive tumors who received gefitinib had a better response rate, disease control rate, and time to progression than patients with P-Akt-negative tumors, suggesting that gefitinib may be most effective in patients with basal Akt activation.

Cited by 353 publications

References 30 publications

The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas

The expression of phospho-AKT1 and phospho-MTOR is associated with a favorable prognosis independent of PTEN expression in intrahepatic cholangiocarcinomas

Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)

Stimulated PI3K-AKT Signaling Mediated through Ligand or Radiation-Induced EGFR Depends Indirectly, but not Directly, on Constitutive K-Ras Activity

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