Characterizing Acquired Resistance to TKIs in EGFR Mutant Lung Adenocarcinoma Cell Lines

  • Jing Sun Vanderbilt University College of Arts and Sciences

Abstract

Traditional treatments for non-small cell lung adenocarcinomas do produce impressive improvements in patient health. Newly developed biologically based treatments exploit the drug-sensitivity conferred by mutations in the epidermal growth factor receptor (EGFR). In adenocarcinomas, cell proliferation and survival depend on mutant EGFR activity. For patients with certain EGFR mutations, treatment with tyrosine kinase inhibitors (TKIs) rather than chemotherapy improves patient survival. However, almost every patient acquires resistance to TKI treatment. About 50% of acquired resistance is because of a secondary mutation in EGFR. MET gene amplification, which allows cells to use MET to activate downstream signals, is another established mechanism. A third known mechanism is epithelial to mesenchymal transition (EMT).
About 30% of all resistance mechanisms still remain unknown. This semester, the HCC2279 EGFR-mutant human adenocarcinoma line was characterized in hopes of discovering new models of resistance. Growth inhibition assays and immunoblotting were used to analyze the effects of treatments and to examine the status of signaling molecules. The HCC2279 resistant line appeared to have an EGFR-independent mechanism and did not seem to use MET as a major mechanism of resistance. The resistant cells continued to grow in the presence of TKI and TKI plus MET inhibitor, and immunoblotting showed that TKIs were capable of completely inhibiting the activation and phosphorylation of EGFR and MET. Signs of EMT were detected via immunoblotting due to a loss of E-cadherin and gain of vimentin, and EMT was corroborated by histological changes such as a loss in resistant cell polarity.

Author Biography

Jing Sun, Vanderbilt University College of Arts and Sciences
Vanderbilt-Ingram Cancer Center Undergraduate Researcher William Pao Lab
Published
08-01-2013
How to Cite
SUN, Jing. Characterizing Acquired Resistance to TKIs in EGFR Mutant Lung Adenocarcinoma Cell Lines. Vanderbilt Undergraduate Research Journal, [S.l.], v. 9, aug. 2013. ISSN 1555-788X. Available at: <http://ejournals.library.vanderbilt.edu/index.php/vurj/article/view/3768>. Date accessed: 18 nov. 2017. doi: https://doi.org/10.15695/vurj.v9i0.3768.
Section
Engineering and Natural Sciences

Keywords

Lung Cancer, Acquired Resistance, Erlotinib, Gefitinib