Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer.

Abstract

BACKGROUND:

Gefitinib, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has activity against approximately 10% of unselected non-small-cell lung cancer (NSCLC) patients. Phosphatidylinositol 3'-kinase (PI3K)/Akt and Ras/Raf/mitogen-activated protein kinase (MAPK), the two main EGFR-signaling pathways, mediate EGFR effects on proliferation and survival. Because activation of these pathways is dependent on the phosphorylation status of the components, we evaluated the association between phosphorylation status of Akt (P-Akt) and MAPK (P-MAPK) and gefitinib activity in patients with advanced NSCLC.

METHODS:

Consecutive patients (n = 106) with NSCLC who had progressed or relapsed on standard therapy received gefitinib (250 mg/day) until disease progression, unacceptable toxicity, or patient refusal. P-Akt and P-MAPK positivity was determined with immunohistochemistry using tumor tissues obtained before any anticancer treatment. Association of P-Akt and time to progression was determined by univariable and multivariable analyses. All statistical tests were two-sided.

RESULTS:

Of the 103 evaluable patients, 51 (49.5%) had tumors that were positive for P-Akt, and 23 (22.3%) had tumors that were positive for P-MAPK. P-Akt-positivity status was statistically significantly associated with being female (P<.001), with never-smoking history (P =.004), and with bronchioloalveolar carcinoma histology (P =.034). Compared with patients whose tumors were negative for P-Akt, patients whose tumors were positive for P-Akt had a better response rate (26.1% versus 3.9%; P =.003), disease control rate (60.9% versus 23.5%; P<.001), and time to progression (5.5 versus 2.8 months; P =.004). Response rate, disease control rate, and time to progression did not differ according to P-MAPK status. The multivariable analysis showed that P-Akt positivity was associated with a reduced risk of disease progression (hazard ratio = 0.58, 95% confidence interval = 0.35 to 0.94).

CONCLUSIONS:

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.

• Authors: Federico Cappuzzo, Elisabetta Magrini, Giovanni Luca Ceresoli, Stefania Bartolini, Elisa Rossi, Vienna Ludovini, Vanesa Gregorc, Claudia Ligorio, Alessandra Cancellieri, Stefania Damiani, Anna Spreafico, Carlo Terenzio Paties, Laura Lombardo, Cesare Calandri, Guido Bellezza, Maurizio Tonato, Lucio Crinò
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 96 Issue 15 Pg. 1133-41 (Aug 04 2004) ISSN: 1460-2105 [Electronic] United States
• PMID: 15292385 (Publication Type: Clinical Trial, Journal Article)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Proto-Oncogene Proteins
• Quinazolines
• Protein-Tyrosine Kinases
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase Kinases
• Gefitinib

Topics

• Adult
• Aged
• Analysis of Variance
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Disease Progression
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Female
• Gefitinib
• Humans
• Immunohistochemistry
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Male
• Middle Aged
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Neoplasm Staging
• Phosphorylation (drug effects)
• Protein Serine-Threonine Kinases (metabolism)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• Quinazolines (pharmacology, therapeutic use)
• Survival Analysis
• Treatment Outcome