Proteomics Profiling Around the AMPK-AKT Signaling Pathway Using the Reverse Phase Array Technology Reveals a Predictive Model for Both Recurrence and Overall Survival in NSCLC as well as Drug Sensitivity in Ovarian Cancer

Abstract

Proteomics Profiling Around the AMPK-AKT Signaling Pathway Using the Reverse Phase Array Technology Reveals a Predictive Model for Both Recurrence and Overall Survival in NSCLC as well as Drug Sensitivity in Ovarian Cancer 

Background: Epithelial Ovarian Cancer (EOC) is the 5th leading cause of cancer related deaths in women. Most patients receive medical care when the disease has spread outside the pelvis due to an absence of systems and the current capability of screening technologies. The standard therapeutic treatment for EOC patients is either to have tumors removed or paclitaxel treatment. Next to EOC, lung cancer is the leading cause of cancer related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers. The standard therapeutic option is chemotherapy with a typical response rate at about 20 – 30% which is relatively low. Due to better screening techniques, more NSCLC are being detected at Stage I than ever before, and chemotherapy with surgery is the most common treatment regimen for this cohort. However, a large subset of Stage I patients are destined to recur with progressive disease, and current clinical pathology techniques cannot distinguish stage I patients into long-term and short-term survival groups. Therefore, a better understanding of the molecular pathways and signaling involved in NSCLC and EOC will produce predictive or therapeutic markers for patients. 

Methods: A literature review was performed that included detailed analysis of three different recent papers explaining studies that used the reverse phase protein array (RPPA) and laser capture microdissection (LCM) in their experimentation. Zupa et al focused on the LBK1-AMPK and AKT-mTOR pathways in NSCLC, Nanjundan et al described RPPA pathway mapping results in node negative recurrent vs non-recurrent NSCLC, and Sereni et al detailed analysis of tumor AKT-mTOR signaling correlation with progression/survival in early stage EOC patients. 

Results: Sereni et al used LCM-RPPA and found clear differences among early and late stage EOC patients as well as drug resistance among advanced EOC patients based on increased AKT-mTOR pathway activation. Including the AKT substrate FOXO1 T24/FOXO3 T32 activation. Zupa et al found that there was clear distinction between short- and long-term survival patients using unsupervised analysis of RPPA based pathway mapping in NSCLC patients. A model featuring Akt was created to predict overall survival patients based on activation of proteins within the model. Lastly, Nanjundan et al found 15 proteins that were shown to be differentially expressed between paired samples. Through these results, a 4-protein model was used to discriminate between a NSCLC tumor or not. A table featuring the AMPK pathway, adhesion pathways, EGFR pathway, and Rb levels was created to show off their association with recurrence. 

Conclusion: Sereni et al revealed carboplatin-paclitaxel resistant EOC patients based on the activation of FOXO1 T24/FOXO3 T32. If further validated in a larger set of patients, patient stratification may be achieved between those that receive paclitaxel treatment and those that do not. Zupa et al showed how protein pathway activation mapping of NSCLC reveals patients with early-stage node negative disease and poor prognosis may be identified by activation of a linked protein signaling event. Stratification of patients and targeted therapies could be conducted if further investigation was done. The results of Nanjundan et al provide evidence of dysregulation among several pathways that are linked to NSCLC pathogenesis and disease recurrence. If further validated, these pathways may have prognostic implications and serve as drug targets. Overall, these studies support the potential of RPPA to identify protein biomarkers that have relevance to ovarian cancer and lung cancer.