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in Serum as Predictors of Poor Response to Gefitinib among Patients with Advanced Non–Small Cell Lung Cancers
1 Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Departments of 2 Molecular and Internal Medicine and 3 Pathology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; 4 Department of Thoracic Surgery, Saitama Cancer Center, Saitama, Japan; and 5 Kanagawa Cancer Center Research Institute, Kanagawa, Japan
Requests for reprints: Yusuke Nakamura, Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5372; Fax: 81-3-5449-5433; E-mail: yusuke{at}ims.u-tokyo.ac.jp.
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Abstract |
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(TGF-), which were identified previously to be expressed at high levels in non–small cell lung cancer (NSCLC) with poor response to gefitinib, were examined by ELISA using blood samples taken from 50 patients with advanced NSCLCs. Of 14 cases that revealed above the cutoff line for amphiregulin in serum, 12 responded poorly to gefitinib, whereas 18 of the 36 cases showing below the cutoff revealed partial response (PR) or stable disease (SD; P = 0.026). Thirteen of 15 patients who were positive for TGF- responded poorly to gefitinib, whereas 18 of the 35 patients with negative TGF- levels turned out to be relatively good responders (P = 0.014). Of 22 patients with positive values for either or both markers, 19 were poor responders. On the other hand, among 28 patients negative for both markers, 17 were classified into the PR or SD groups (P = 0.001). Gefitinib-treated NSCLC patients whose serum amphiregulin or TGF- was positive showed a poorer tumor-specific survival (P = 0.037 and 0.002, respectively, by univariate analysis) compared with those whose serum amphiregulin or TGF- concentrations were negative. Multivariate analysis showed an independent association between positivity for TGF- and shorter survival times among NSCLC patients treated with gefitinib (P = 0.034). Amphiregulin or TGF- positivity in NSCLC tissues was significantly higher in male, nonadenocarcinomas, and smokers. Our data suggest that the status of amphiregulin and TGF- in serum can be an important predictor of the resistance to gefitinib among patients with advanced NSCLC. |
Introduction |
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Approximately 37,000 patients with advanced NSCLC have been treated with this drug in Japan since its approval (7). Although gefitinib has been effective for many of those Japanese patients, improving their prognosis and quality of life, 
60% of them have shown no improvement in symptoms. Furthermore, the incidence of severe gefitinib-induced acute interstitial pneumonia can be as high as 5.4% (8). Obviously, a method that would allow physicians to select patients likely to respond well to gefitinib would be highly desirable. Unfortunately, no single factor examined thus far, including somatic mutations of EGFR, has been able to perfectly determine the susceptibility of patients to gefitinib treatment from the viewpoint of disease control or survival benefit [i.e., they have failed to discriminate certain proportion of potential long-term survivors, including stable disease (SD) patients from short-term survivors]. The presence of EGFR mutations can usually predict patients likely to show partial response (PR) to gefitinib, but this approach has no power to indicate patients keeping stable condition who could receive a survival benefit (9–13).
We recently identified dozens of genes associated with sensitivity to gefitinib through statistical analysis of gene expression profiles of advanced NSCLCs and introduced a gefitinib response scoring system based on expression of selected genes that had shown the most significant differences in expression levels between PR and progressive disease (PD) groups (14). The gefitinib response scoring system successfully predicted all of additional "test" cases (PR and PD) in accordance with their clinical responses to gefitinib. Moreover, this system was able to separate SD into two groups, one representing patients who succeeded in maintaining the tumor-static effect for a long period and the other representing patients who failed to do so.
However, analysis of expression profiles or mutations requires acquisition of tissue specimens by surgery or biopsy, which is not routine in cases of advanced NSCLC, and sometimes these procedures themselves cause various complications. Hence, practical clinical tests using serologic markers that can predict the sensitivity or resistance of lung cancers to gefitinib therapy are urgently required. As a step toward that goal, the cDNA microarray analysis mentioned above revealed that genes encoding two EGFR ligands, amphiregulin and transforming growth factor- (TGF-), were among those overexpressed in tumor tissues obtained from nonresponders to gefitinib (14).
We report here our attempt to establish ELISA assays for these two protein markers in human serum. Our results suggest that circulating amphiregulin and TGF- could be clinically applicable as indicators for an unfavorable response to gefitinib by identifying patients with a higher probability of resistance to the drug.
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Materials and Methods |
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20 years, had performance status (PS) of 0, 1, or 2, and had no significant abnormalities in liver or kidney functions. Treatment was continued until the patient was dropped from the study due to progression of disease, intolerable toxicity, or withdrawal of consent. Serum was obtained within 1 week before administration of gefitinib and stored at –80°C. Among the 50 patients whose serum samples were used for ELISA assays, we obtained formalin-fixed primary NSCLC tissue samples from 13 patients treated with gefitinib for their recurrent and chemoresistant diseases after they had undergone surgery at the initial treatment (nine adenocarcinomas, three squamous cell carcinomas, and one adenosquamous cell carcinoma). The use of all clinical materials obtained with written informed consent was approved by the Institutional Research Ethics Committee. Objective tumor responses at every evaluable lesion were assessed every 4 weeks after the beginning of treatment according to criteria outlined elsewhere (14). After 4 months of treatment, the best overall response was evaluated for each patient based on the following definitions: complete response (CR), patients who qualified as CR at two sequential examination points with an interval of at least 28 days between them; PR, patients judged as PR or better at two sequential examination points with an interval of at least 28 days between them; SD, patients who were SD or better at two sequential examination points at least 28 days apart but who did not qualify as CR or PR. The first judgment of SD must be done at or after the first tumor assessment point 28 days after the start of gefitinib treatment; and PD, the patients determined as PD at or before the first tumor assessment point (28 days after the start of gefitinib treatment).
ELISA. TGF- concentrations in serum were measured using a commercially available enzyme test (TGF- ELISA kit, R&D Systems, Minneapolis, MN) as described previously (14, 15). For detection of soluble amphiregulin in serum, 96-well flexible microtiter plates (Nalge Nunc International, Rochester, NY) were coated with 1 ng/mL capturing antibody (anti-amphiregulin monoclonal antibody, R&D Systems) overnight. Wells were blocked with 300 µL PBS (pH 7.4) containing 1% bovine serum albumin, 5% sucrose, and 0.05% NaN3 for 2 hours and then incubated for 2 hours with serum samples diluted 1:3 in PBS (pH 7.4) containing 1% bovine serum albumin. After washing with PBS (pH 7.4) containing 0.05% Tween 20, the wells were incubated for 2 hours with 100 ng/mL biotin-conjugated polyclonal anti-amphiregulin antibody (R&D Systems) followed by reaction with avidin-conjugated peroxidase (DakoCytomation, Glostrup, Denmark) using a substrate reagent (R&D Systems). The color reaction was stopped by addition of 2 N sulfuric acid. Color intensity was determined by a photometer at a wavelength of 450 nm with a reference wavelength of 630 nm. A standard curve was drawn for each plate using recombinant amphiregulin or TGF- proteins for reference. Minimum detection limits of the assays for serum amphiregulin and TGF- were 10.1 and 3.1 pg/mL, respectively. We verified by Western blot or immunoprecipitation assays that these commercial anti-amphiregulin and anti-TGF- antibodies could specifically detect individual proteins using malignant pleural effusions obtained from five patients with advanced NSCLC whose serum amphiregulin/TGF- had been positive.
EGFR mutation. EGFR mutations at region of exons 18 to 21 of EGFR, which was reported as a hotspot of mutation (refs. 9–13; from p-loop to activation loop, codon position 709-870), were screened in surgically resected tumor tissues available from the 13 NSCLC patients who were treated with gefitinib (see above). Genomic DNAs were extracted as described previously (16). Briefly, cancer tissues were immediately resuspended in 20 µL buffer containing 10 mmol/L Tris-HCl (pH 8.3), 2.5 mmol/L MgCl2, 50 mmol/L KCl, 0.45% NP40, 0.45% Tween 20, and 0.1 mg/mL proteinase K and were incubated overnight at 55°C. The mixture was boiled for 10 minutes to inactivate the proteinase K and was used for PCR. PCR-based direct sequencing experiments were carried out with the same primers for exons 18 to 21 as described elsewhere (12).
Immunohistochemistry and tissue microarray. An independent set of 449 formalin-fixed primary tumors (285 adenocarcinomas, 121 squamous cell carcinomas, 28 large-cell carcinomas, and 15 adenosquamous cell carcinomas) and adjacent normal lung tissue samples from patients undergoing surgery at Saitama Cancer Center (Saitama, Japan) were used in this study. The histologic patterns of adenocarcinoma were divided into four distinctive subtypes: bronchioloalveolar carcinoma, acinar subtype, papillary subtype, and solid adenocarcinoma with mucin. The pathologic stage was determined according to the classification of the Union Internationale Contre le Cancer (17). Tumor tissue microarrays were constructed using these 449 formalin-fixed primary lung cancers as published previously (15).
To investigate levels of amphiregulin and TGF- proteins in clinical samples with clinicopathologic variables, we stained the sections using Envision+ kit/horseradish peroxidase (HRP; DakoCytomation). After blocking, the following antibodies were applied in this study: a rabbit polyclonal anti-human amphiregulin antibody (Ab-1, Lab Vision Corp., Fremont, CA) used at 1:40 dilution and a mouse monoclonal anti-TGF- antibody (Ab-2, Oncogene Science, Manhasset, NY) used at 1:80 dilution. The sections were incubated with HRP-labeled antirabbit or antimouse immunoglobulin G as the secondary antibody. Substrate chromogen was added and the specimens were counterstained with hematoxylin. Three independent investigators assessed amphiregulin and TGF- positivity semiquantitatively without prior knowledge of the clinical follow-up data. The intensity of cytoplasmic staining was scored using the following criteria: 0 (absent), 1+ (positive), and 2+ (strongly positive). We also scored the pattern of amphiregulin staining (cytoplasmic, nuclear, or both) as reported previously (18, 19).
Statistical analysis. Statistical analyses were done using the StatView statistical program (SAS, Cary, NC) to compare patient characteristics with responses to therapy. Associations between clinicopathologic variables, including positivity for amphiregulin and/or TGF- in serum, and the response to gefitinib were compared by Fisher's exact tests. Tumor-specific survival and 95% confidence intervals (95% CI) were evaluated with the Kaplan-Meier method, and differences between the two groups were evaluated with the log-rank test. Risk factors associated with the prognosis were evaluated using Cox proportional hazards regression model with a step-down procedure. Proportional hazards assumptions were checked and satisfied; only those variables with statistically significant results in univariate analysis were included in a multivariate analysis. The criterion for removing a variable was the likelihood ratio statistic, which was based on the maximum partial likelihood estimate (default P of 0.05 for removal from the model).
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Results |
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levels, clinicopathologic features, and response to gefitinib therapy. In our recent study using a cDNA microarray to analyze gene expression in tumors from 33 patients with advanced NSCLC who had been treated with second-line to seventh-line gefitinib monotherapy, amphiregulin and TGF- were found to be significantly overexpressed in PD cases but hardly detectable in PR cases (permutational Ps of 9.3 x 10–12 and 0.0095, respectively; ref. 14). Hence, to establish a routine and less invasive laboratory test for prediction of drug response, we attempted to use two protein markers and attempted to establish the serologic markers. We applied ELISA assays for both proteins using serum samples from an independent set of 50 other NSCLC patients treated with gefitinib. Judgments of "positive" or "negative" were based on measured concentrations of each protein that fell above or below cutoff values (93.8 pg/mL for amphiregulin and 15.6 pg/mL for TGF-), which had been set by drawing receiver-operated characteristic curves according to optimal diagnostic accuracy and likelihood ratios discriminating PD cases from disease-controlled cases (PR + SD). Fourteen (28.0%) of the 50 serum samples were judged as positive for amphiregulin and 15 (30.0%) patients were positive for TGF- according to these cutoff values (Fig. 1).
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positivity and response to gefitinib therapy in this group of patients. Twelve (40.0%) serum samples from the 30 PD patients were positive for amphiregulin, whereas 18 of 20 (90.0%) samples from disease-controlled (PR or SD) patients were negative (P = 0.026 by Fisher's exact test). Thirteen of 30 (43.3%) samples from PD patients were positive for TGF-, whereas 18 of 20 (90.0%) samples from PR or SD patients were negative (P = 0.014 by Fisher's exact test). At least one of the two proteins was positive in 19 of 30 (63.3%) serum samples from PD patients, whereas 17 of 20 (85.0%) samples from PR + SD patients were negative (P = 0.001 by Fisher's exact test), indicating that a combined assay using both amphiregulin and TGF- should be a good predictor for poor response in 63% of PD cases. The false-positive rate for indicating PD response was only 15.0%.
Table 1 also shows associations between clinicopathologic factors and responses to gefitinib therapy among the 50 patients. In this study, both performance status (0/1 versus 2; P = 0.037 by Fisher's exact test) and smoking history (current and former smoker versus never-smoker; P = 0.035 by Fisher's exact test) as well as amphiregulin and/or TGF- positivity were significantly associated with the response to gefitinib. As mentioned above, 12 of 14 patients with amphiregulin-positive values as well as 13 of 15 patients with TGF--positive scores revealed poor response to gefitinib therapy. Of 22 patients with positive values for either marker, 19 were judged as PD.
The median survival time of amphiregulin-negative patients treated with gefitinib was significantly longer than that of amphiregulin-positive patients (P = 0.032 by log-rank test; Fig. 2A). The same was true of TGF--negative patients (P = 0.001 by log-rank test; Fig. 2B). We also used univariate analysis to evaluate associations between patient prognosis and other factors, including age, gender (male versus female), PS (0/1 versus 2), disease stage (IIIB versus other stages), smoking history (current and former smoker versus never smoker), histologic classification (adenocarcinoma versus other histologic types), serum amphiregulin status (positive versus negative), and serum TGF- status (positive versus negative; Table 2). Among these variables, serum amphiregulin positivity [odds ratio (OR), 2.235; 95% CI, 1.050-4.761; P = 0.037], serum TGF- positivity (OR, 3.315; 95% CI, 1.557-7.059; P = 0.002), and PS (OR, 6.707; 95% CI, 2.544-17.682; P < 0.001) were significantly associated with poor prognosis. However, multivariate analysis revealed that serum TGF- status (OR, 2.457; 95% CI, 1.072-5.625; P = 0.034) and PS (OR, 4.792; 95% CI, 1.420-16.171; P = 0.012) were significant independent prognostic factors for advanced NSCLC patients who received gefitinib therapy.
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, we carried out PCR-based direct sequencing of the EGFR tyrosine kinase domain (exons 18-21) using tumors from 13 patients whose sera were also analyzed by ELISA. As shown in Table 3, EGFR mutations were detected in 4 of 8 (50%) patients showing PR or SD condition after gefitinib treatment and in 2 of 5 (40%) PD cases, indicating that there was no significant association between EGFR mutations and the levels of serum amphiregulin and TGF-.
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in unselected lung cancer tissues. To investigate the clinical significance of amphiregulin and TGF- overexpression, we also examined the expression of amphiregulin and TGF- proteins by means of tissue microarrays containing NSCLC tissues from unselected 449 patients who underwent surgical resection. Amphiregulin was mainly detected at cytoplasm and/or nucleus of tumor cells as reported elsewhere (18, 19). TGF- was mainly stained at the cytoplasm of tumor cells. As shown in Table 4, gender (higher in male; P < 0.001 by Fisher's exact test), histologic type (higher in nonadenocarcinoma; P < 0.001 by Fisher's exact test), and smoking history (higher in current and former smokers; P < 0.001 by Fisher's exact test) were significantly associated with the amphiregulin positivity. A similar tendency was observed in the TGF- analysis (higher in male, P = 0.001; higher in nonadenocarcinoma, P < 0.001; and higher in current and former smokers, P = 0.005 by Fisher's exact test). The amphiregulin positivity was significantly higher in nonbronchioloalveolar (P = 0.004) and nonpapillary (P = 0.011) subtypes of adenocarcinoma, whereas no significant difference in the TGF- positivity was observed.
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-negative patients was longer than that of the negative patients (P = 0.029 by log-rank test; Fig. 2D). We also applied univariate analysis to evaluate associations between patient prognosis and several factors, including age, gender, pT stage (T1 + T2 versus T3 + T4), pN stage (N0 + N1 versus N2 + N3), smoking history, histologic classification, amphiregulin status (positive versus negative), and TGF- status. Among these variables, amphiregulin positivity, TGF- positivity, elderly, male, nonadenocarcinoma histology, pT stage, and pN stage were significantly associated with poor prognosis (Table 5). However, multivariate analysis revealed that neither amphiregulin nor TGF- status was an independent prognostic factor for surgically treated NSCLC patients who were not treated with gefitinib (Table 5).
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Discussion |
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Analyses of mutations or expression profiles are time-consuming procedures and require biopsy samples containing a sufficient number of cancer cells. Because patients with advanced NSCLC are rarely candidates for surgical resection of their tumors and invasive biopsy for pathologic diagnosis is not essential for selection of their treatment protocols, the above approaches are not appropriate for routine diagnosis of drug response. In fact, the incidence of major complications related to transbronchial biopsy is reportedly as high as 0.5% to 6.8% (21). Hence, we considered it urgent to establish a safe and less invasive system for predicting chemosensitivity of individual patients, such as a serologic test, which would be readily available at any hospital.
We found recently that amphiregulin and TGF-, both encoding ligands for EGFR and other ErbBs, were significantly overexpressed in tumor cells of nonresponders but hardly detectable in those of responders to gefitinib (14). Examination of the serum levels of amphiregulin and TGF- in a subset of patients with advanced NSCLC revealed that amphiregulin and TGF- proteins in the serum of such patients might have a high diagnostic value for predicting poor response to gefitinib. The positivity of these proteins in serum of nonresponders was 12 of 30 (40.0%) for amphiregulin and 13 of 30 (43.3%) for TGF-. Furthermore, a combination of the two markers improved the overall sensitivity for detection of nonresponders to 63.3%. One of the important advantages of a prediction system using these two markers is its ability to specifically discriminate PD cases from PR or SD patients compared with analysis of EGFR mutation that mainly selects patients with PR to gefitinib but has no significant power to indicate patients with SD (9–13). In fact, statistical analysis supports the hypothesis that the levels of serum amphiregulin and TGF- were biologically independent of EGFR mutation status (Table 3).
Although further evaluation of these serologic markers in clinical settings will be necessary, eventually they should, in combination with a limited number of other possible markers that we found to be significantly positive in PD patients in our microarray analysis (14), enable laboratories to more precisely select in advance the patients who will actually benefit from gefitinib treatment. The prospective trial to evaluate the reliability of the serum marker–based prediction system is in progress in our institute.
The present study also showed that the survival time of patients with positive values for serum amphiregulin or TGF- was significantly shorter than for patients with negative values. In particular, diagnosis of these markers in serum seemed to be independently related to poor prognosis. An initial analysis of the primary end point of a phase III trial (Iressa Survival Evaluation in Lung Cancer with 1,692 patients; http://www.astrazeneca.com/pressrelease/4245.aspx) revealed that gefitinib failed to significantly prolong survival in comparison with placebo in the overall population (hazard ratio, 0.89; P = 0.11; median, 5.6 versus 5.1 months) or in patients with adenocarcinoma (hazard ratio, 0.83; P = 0.07; median, 6.3 versus 5.4 months), although there was a statistically significant improvement in objective response rate in these populations, and there were survival benefits in a prospective subgroup of patients of Oriental origin or who had never smoked. Our own results suggest that serum concentrations of amphiregulin and/or TGF- could be useful for selection of patients who are likely to respond poorly to gefitinib and receive no clinical benefit from it while extending the survival benefit of gefitinib to a larger population of patients who should in fact receive this treatment. At present, detecting the serum amphiregulin and TGF- is the only routine and significant predictor for poor response of advanced NSCLCs to gefitinib treatment. In this sense, serum amphiregulin and TGF- positivities could be useful for decision of the gefitinib treatment option, providing that a standardized diagnostic kit available at every hospital is developed and its validation in a larger clinical setting is completed.
The significance of the EGFR ligand autocrine loop in growth and survival of lung cancer cells is indisputable (22, 23). However, the role of amphiregulin and TGF- in the development and progression of lung cancer is not well understood, although several lines of evidence suggest that overexpression of amphiregulin is associated with shortened survival of patients with NSCLC (22). Our data also revealed that the expression of amphiregulin and TGF- proteins in NSCLC tissues is likely to correlate with a poor prognosis of surgically treated patients to a certain extent. In addition, male, nonadenocarcinoma, and smoking history were associated with amphiregulin and TGF- positivity in NSCLC tissues, and some histologic subtypes of adenocarcinoma (nonpapillary and nonbronchioloalveolar subtypes) were associated with amphiregulin positivity. Recently, other investigators reported that gefitinib was particularly effective in adenocarcinoma, especially the dominant papillary and/or bronchioloalveolar subtype (6, 20); their data independently suggested the possible relationship between amphiregulin/TGF- expression and histologic types that are resistant to gefitinib. On the other hand, antiapoptotic activity of amphiregulin in human lung adenocarcinoma cells was reported recently (23). To investigate whether the antiapoptotic activity of amphiregulin leads to resistance of NSCLC cells to gefitinib therapy, we previously did a biological assay using a gefitinib-sensitive but amphiregulin-nonexpressing NSCLC cell line, PC-9, and found that the antitumor activity of gefitinib on PC-9 cells was decreased dramatically by autocrine secretion of amphiregulin (14). That evidence strongly suggests that although growth factor signaling by the EGFR is extremely complicated at every step because of the multiplicity of ligands, dimerization partners, effectors, and downstream pathways (22, 23), amphiregulin might be a principal activator of the ligand-receptor autocrine pathway that leads to the resistance of cancer cells to gefitinib.
In conclusion, the present study showed that the status of amphiregulin and TGF- in serum could be an important predictor of the response of NSCLCs to gefitinib. Measurement of serum amphiregulin and TGF- levels is obviously a routinely feasible, relatively noninvasive, and inexpensive method of predicting response to this drug.
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Acknowledgments |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 5/ 5/05. Revised 7/21/05. Accepted 8/17/05.
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C. Suzuki, K. Takahashi, S. Hayama, N. Ishikawa, T. Kato, T. Ito, E. Tsuchiya, Y. Nakamura, and Y. Daigo Identification of Myc-associated protein with JmjC domain as a novel therapeutic target oncogene for lung cancer Mol. Cancer Ther., February 1, 2007; 6(2): 542 - 551. [Abstract] [Full Text] [PDF]
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S. Hayama, Y. Daigo, T. Kato, N. Ishikawa, T. Yamabuki, M. Miyamoto, T. Ito, E. Tsuchiya, S. Kondo, and Y. Nakamura Activation of CDCA1-KNTC2, Members of Centromere Protein Complex, Involved in Pulmonary Carcinogenesis Cancer Res., November 1, 2006; 66(21): 10339 - 10348. [Abstract] [Full Text] [PDF]
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K. Takahashi, C. Furukawa, A. Takano, N. Ishikawa, T. Kato, S. Hayama, C. Suzuki, W. Yasui, K. Inai, S. Sone, et al. The Neuromedin U-Growth Hormone Secretagogue Receptor 1b/Neurotensin Receptor 1 Oncogenic Signaling Pathway as a Therapeutic Target for Lung Cancer Cancer Res., October 1, 2006; 66(19): 9408 - 9419. [Abstract] [Full Text] [PDF]
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H. Su, C. Bodenstein, R. A. Dumont, Y. Seimbille, S. Dubinett, M. E. Phelps, H. Herschman, J. Czernin, and W. Weber Monitoring Tumor Glucose Utilization by Positron Emission Tomography for the Prediction of Treatment Response to Epidermal Growth Factor Receptor Kinase Inhibitors. Clin. Cancer Res., October 1, 2006; 12(19): 5659 - 5667. [Abstract] [Full Text] [PDF]
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J. Castillo, E. Erroba, M. J. Perugorria, M. Santamaria, D. C. Lee, J. Prieto, M. A. Avila, and C. Berasain Amphiregulin contributes to the transformed phenotype of human hepatocellular carcinoma cells. Cancer Res., June 15, 2006; 66(12): 6129 - 6138. [Abstract] [Full Text] [PDF]
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 S. Kalyankrishna and J. R. Grandis Epidermal Growth Factor Receptor Biology in Head and Neck Cancer J. Clin. Oncol., June 10, 2006; 24(17): 2666 - 2672. [Abstract] [Full Text] [PDF]
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C. Suzuki, Y. Daigo, N. Ishikawa, T. Kato, S. Hayama, T. Ito, E. Tsuchiya, and Y. Nakamura ANLN Plays a Critical Role in Human Lung Carcinogenesis through the Activation of RHOA and by Involvement in the Phosphoinositide 3-Kinase/AKT Pathway Cancer Res., December 15, 2005; 65(24): 11314 - 11325. [Abstract] [Full Text] [PDF]
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