Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer.
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.
Cappuzzo
Federico
F
Department of Oncologic Sciences, Bellaria-Maggiore Hospital, Bologna, Italy. federico.cappuzzo@ausl.bo.it
Magrini
Elisabetta
E
Ceresoli
Giovanni Luca
GL
Bartolini
Stefania
S
Rossi
Elisa
E
Ludovini
Vienna
V
Gregorc
Vanesa
V
Ligorio
Claudia
C
Cancellieri
Alessandra
A
Damiani
Stefania
S
Spreafico
Anna
A
Paties
Carlo Terenzio
CT
Lombardo
Laura
L
Calandri
Cesare
C
Bellezza
Guido
G
Tonato
Maurizio
M
Crinò
Lucio
L
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009367:Neoplasm Staging; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D011505:Protein-Tyrosine Kinases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D000077156:Gefitinib