Abstract 725: In vivo imaging and quantitative proteomics to study responsiveness to EGFR targeted therapy.
Authors: Venugopalan Abhilash , Gang Niu , Guo Jinxia , Maity Tapan , Zhang Xu , Cultraro Constance , Chen Xiaoyuan , Guha Udayan 
Published: August 2014

Lung cancer is the leading cause of cancer related mortality in the United States and is the most common cancer worldwide. Somatic mutations in the kinase domain of EGFR such as in-frame deletion of LREA amino acids in exon 19 and L858R point mutation in exon 21 largely account for 15-30% of lung adenocarcinoma. Although lung cancer patients carrying either of these mutations respond dramatically to EGFR-directed tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib, acquired resistance to these drugs has been the main obstacle in treating these patients for the long term. Secondary mutation at the gatekeeper residue of the kinase domain (T790M) of EGFR accounts for drug resistance in about 50% of patients.

We have used doxycycline inducible mutant EGFR transgenic mice to model human lung adenocarcinoma that is sensitive and resistant to TKIs. Our overall goal is to examine the treatment response to EGFR-directed TKIs in lung adenocarcinoma harboring various EGFR mutants. Our approach is aimed to identify imaging surrogates and proteomics profile of treatment response in mouse models of mutant EGFR-driven lung tumorigenesis.

In this study, we have used transgenic mice that express exon 19 deletion mutant, L858R mutant, and L858R/T790M double mutant in type II pneumocytes upon doxycycline induction. Tumor burden in these mice was monitored by serial MRI imaging. Each group of mice with significant tumor burden was treated with erlotinib, a reversible EGFR inhibitor, BIBW-2992, an irreversible EGFR/ERBB2 dual inhibitor, or a combination of BIBW-2992 and cetuximab, an antibody directed against EGFR followed by 2[18F]Fluoro-2-deoxy-d-glucose (FDG)-PET imaging to assess any tumor regression. We observed a significant reduction of 18FDG uptake by tumors after the treatment with erlotinib in L858R mutant mice. However, in L858R/T790M mutant mice, no significant reduction of 18FDG uptake was observed upon treatment with erlotinib and BIBW-2992 had only mild effect. We are currently designing rational combination treatments based on the response in 18FDG-PET imaging. Finally, we are performing global phosphoproteomic analysis using quantitative mass spectrometry and immunohistochemistry with phospho-specific antibodies on tumor tissue before and after various treatments and correlating with the response in PET imaging. Results from these experiments will help us identify potential biomarkers (imaging and proteomic) of treatment response in lung adenocarcinoma driven by both TKI-sensitizing and resistant mutants of EGFR.

Citation Format: Abhilash Venugopalan, Niu Gang, Jinxia Guo, Tapan Maity, Xu Zhang, Constance Cultraro, Xiaoyuan Chen, Udayan Guha. In vivo imaging and quantitative proteomics to study responsiveness to EGFR targeted therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 725. doi:10.1158/1538-7445.AM2013-725