Targeting β-catenin signaling in combination with EGFR TKI enhances progression free survival and overall survival of EGFR mutant NSCLC
T2017-425 The discovery of a novel treatment for EGFR TKI drug resistance in NSCLC.
Non-small cell lung cancer (NSCLC), which accounts for 85% of all lung cancers, is one of the leading causes of cancer-related death. Substantial progress has been made in the management of NSCLC as several driver mutations have been identified in cell communication pathways involved in lung tumoriogenesis. One of the major pathways that is often targeted in developmental treatments with the use of inhibitors are proteins called tyrosine kinases. Tyrosine kinase inhibitors (TKI's) are primarily used against tumors with specific activating mutations in the epidermal growth factor receptor (EGFR). However, treatment with first and even second generation TKI's results in variable clinical responses and is not considered curative as tumor eradication is never achieved. Researchers have identified that EGFR mutant lung cancer cells avoid eradication through pre-existing subclones. Furthermore, treatment with a first generation drug, such as erlotinib, which is designed to target the subclones, is not completely effective and a subpopulation of cells survives. The inherent 'adaptive persistence of this cancer type is a mechanism that needs to be elucidated for the treatment of this complex tumor type.
Dr. Rajeswara Rao Arasada and colleagues at The Ohio State University have identified a novel pathway that facilitates the survival of the subset of cells that make up the 'adaptive persisters'. The researchers discovered that with EGFR inhibition, there is a rapid induction of β-catenin signaling, a protein that interacts with a cell signaling protein Notch3. Furthermore, they have demonstrated that with pre-clinical xenograft mouse model that the combination of EGFR-TKI and β-catenin inhibitor, PRI-724, blocks this phenomenon, thus decreasing tumor burden and improving both recurrence free survival and overall survival.
Based on their initial pre-clinical discovery, Dr. Arasada and colleagues have developed a method for clinically diagnosing EGFR TKI drug resistance in a subject with an EGFR mutated NSCLC through a simple blood test. The blood test uses plasminogen activator inhibitor-1 (PAI-1) as a prognostic marker to determine the degree of resistance in the patient before and after treatment. Additionally, the researchers have developed a method for treating EGFR TKI drug resistance through the use of an effective dose of β-catenin inhibitor. With these novel and exciting breakthroughs, Dr. Arasada and colleagues have developed both a novel diagnosis and treatment for EGFR TKI drug resistance in NSCLC that will undoubtedly impact the future treatment of NSCLC.
- Oncology therapeutic drug treatments
- Treatment-resistant tumors
- Novel diagnosis and treatment of drug-resistant cancer
- Potential reduction in cancer-related death