Profiling of phospho-AKT, phospho-mTOR, phospho-MAPK and EGFR in non-small cell lung cancer
Haruhisa Kitano1, Joon-Yong Chung, Kris Ylaya
1Tissue Array Research Program, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland (HK, JYC, KY, CC, SMH).
Abstract:
Activation of numerous pathways has been documented in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) has emerged as a common therapeutic target. The mitogen-activated protein kinase (MAPK) and AKT signaling pathways are downstream of EGFR and deregulated via genetic and epigenetic mechanisms in many human cancers. We evaluated selected markers in the EGFR pathway with reference to outcome. Tissues from 220 cases of NSCLC patients presented in a tissue microarray were assayed with immunohistochemistry for phosphorylated AKT, phosphorylated MAPK, phosphorylated mTOR, and EGFR and then quantified by automated image analysis. Individually, the biomarkers did not predict. Combined as ratios, p-mTOR/p-AKT, and p-MAPK/EGFR function as prognostic markers of survival (p=0.008 and p=0.029, respectively), however, no significance was found after adjustment (p=0.221, p=0.103). The sum of these ratios demonstrates a stronger correlation with survival (p<0.001) and remained statistically significant after adjustment (p=0.026). The algebraic combination of biomarkers offer the capacity to understand factors that predict outcome better than current approaches of evaluating biomarkers individually or in pairs. Our results show the sum of p-mTOR/p-AKT and p-MAPK/EGFR is a potential predictive marker of survival in NSCLC patients.
Insights
Combining specific biomarkers in non-small cell lung cancer (NSCLC) pathways, particularly the sum of p-mTOR/p-AKT and p-MAPK/EGFR ratios, shows significant prognostic value for patient survival. This approach offers improved prediction over individual markers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Non-small cell lung cancer (NSCLC) involves numerous activated signaling pathways.
- Epidermal growth factor receptor (EGFR) is a key therapeutic target in NSCLC.
- Mitogen-activated protein kinase (MAPK) and AKT pathways are downstream of EGFR and frequently deregulated in cancer.
Purpose of the Study:
- To evaluate selected biomarkers within the EGFR pathway as predictors of outcome in NSCLC.
- To investigate the prognostic significance of individual biomarkers and their combinations.
Main Methods:
- Immunohistochemistry was used to assay EGFR pathway markers (phosphorylated AKT, MAPK, mTOR, and EGFR) in 220 NSCLC tissue samples.
- Automated image analysis quantified biomarker expression.
- Biomarkers were analyzed individually, as ratios (p-mTOR/p-AKT, p-MAPK/EGFR), and as a combined sum of ratios.
Main Results:
- Individual biomarkers did not predict survival.
- The ratios p-mTOR/p-AKT and p-MAPK/EGFR showed initial prognostic value but lost significance after adjustment.
- The sum of these ratios demonstrated a strong correlation with survival and remained statistically significant after adjustment.
Conclusions:
- Algebraic combinations of biomarkers, specifically the sum of p-mTOR/p-AKT and p-MAPK/EGFR ratios, can predict survival in NSCLC patients.
- This combined biomarker approach offers superior predictive capacity compared to evaluating markers individually or in pairs.
- The sum of p-mTOR/p-AKT and p-MAPK/EGFR is a potential predictive marker for NSCLC patient survival.
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