The discovery of somatic mutations in epidermal growth receptor (EGFR) in patients who show dramatic response to reversible EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib has introduced the concept of personalized therapy in lung cancer treatment. However, resistance to the inhibitors emerges within one to two years. The secondary EGFR-T790M mutation, in the gate-keeper position of the tyrosine kinase domain, is present in more than 50% of lung cancers with acquired resistance to gefitinib or erlotinib. Since treatment options for these patients are currently limited, novel strategies to prevent or overcome acquired resistance to EGFR TKIs are sorely needed. We have demonstrated that -catenin is upregulated and activated in lung cancer cells harboring EGFR mutations including EGFR-T790M. As aberrant activation of -catenin signaling can lead to human cancers, we hypothesize that -catenin plays an essential role in lung tumorigenesis caused by EGFR mutants and inhibiting its activation alone or in combination with irreversible EGFR inhibitors may be an alternative strategy to overcome resistance to gefitinib or erlotinib. Therefore, our specific aims are to: (1) Investigate the mechanisms by which EGFR mutants lead to accumulation, nuclear translocation, and activation of ?-catenin; (2) Investigate whether activation of -catenin is required for EGFR- T790M-driven lung cancer formation/progression in vivo; and (3) Evaluate the effectiveness of -catenin inhibition as a novel therapeutic strategy to overcome resistance to erlotinib or gefitinib. We believe that the experiments proposed here will provide novel insights into the detailed mechanisms by which EGFR mutations cause tumorigenesis and innovative approaches to overcome resistance to gefitinib or erlotinib, significantly impacting care of patients with lung cancer in the near future.
Lung cancer is number one cause of cancer-related deaths in the United States. Our major goal is to investigate the role of the -catenin signaling in tumors resistant to targeted therapies. A better understanding of lung tumorigenesis will lead to novel therapeutic strategies in the future.
|VanderLaan, Paul A; Rangachari, Deepa; Majid, Adnan et al. (2018) Tumor biomarker testing in non-small-cell lung cancer: A decade of change. Lung Cancer 116:90-95|
|Jorge, Susan E; Lucena-Araujo, Antonio R; Yasuda, Hiroyuki et al. (2018) EGFR Exon 20 Insertion Mutations Display Sensitivity to Hsp90 Inhibition in Preclinical Models and Lung Adenocarcinomas. Clin Cancer Res 24:6548-6555|
|Rangachari, Deepa; Le, Xiuning; Shea, Meghan et al. (2017) Cases of ALK-Rearranged Lung Cancer with 5-Year Progression-Free Survival with Crizotinib as Initial Precision Therapy. J Thorac Oncol 12:e175-e177|
|Takenaka, Tomoya; Katayama, Miku; Sugiyama, Ayaka et al. (2017) Gefitinib Enhances Mitochondrial Biological Functions in NSCLCs with EGFR Mutations at a High Cell Density. Anticancer Res 37:4779-4788|
|Gonzalez, David; Luyten, Annouck; Bartholdy, Boris et al. (2017) ZNF143 protein is an important regulator of the myeloid transcription factor C/EBP?. J Biol Chem 292:18924-18936|
|VanderLaan, Paul A; Rangachari, Deepa; Mockus, Susan M et al. (2017) Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: Correlation with clinical outcomes. Lung Cancer 106:17-21|
|Rangachari, Deepa; VanderLaan, Paul A; Shea, Meghan et al. (2017) Correlation between Classic Driver Oncogene Mutations in EGFR, ALK, or ROS1 and 22C3-PD-L1 ?50% Expression in Lung Adenocarcinoma. J Thorac Oncol 12:878-883|
|Forloni, Matteo; Gupta, Romi; Nagarajan, Arvindhan et al. (2016) Oncogenic EGFR Represses the TET1 DNA Demethylase to Induce Silencing of Tumor Suppressors in Cancer Cells. Cell Rep 16:457-471|
|Lucena-Araujo, Antonio R; Moran, Jason P; VanderLaan, Paul A et al. (2016) De novo ALK kinase domain mutations are uncommon in kinase inhibitor-naïve ALK rearranged lung cancers. Lung Cancer 99:17-22|
|Kobayashi, Susumu S; Vali, Shireen; Kumar, Ansu et al. (2016) Identification of myeloproliferative neoplasm drug agents via predictive simulation modeling: assessing responsiveness with micro-environment derived cytokines. Oncotarget 7:35989-36001|
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