Abstract 933: Modeling acquired resistance to EGFR-directed therapies in mouse models of lung cancer
Autor: | Katerina Politi, William Pao, Zhongming Zhao, Jungfeng Xia, Valentina Pirazzoli, Elisa de Stanchina |
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Rok vydání: | 2013 |
Předmět: | |
Zdroj: | Cancer Research. 73:933-933 |
ISSN: | 1538-7445 0008-5472 |
Popis: | Seventy percent of patients with Epidermal Growth Factor Receptor (EGFR) mutant lung cancer respond to treatment with the tyrosine kinase inhibitors (TKIs) erlotinib or gefitinib. Despite this high response rate, patients almost inevitably develop resistance to these drugs on average within a year of starting drug treatment. Acquired resistance to EGFR TKIs is most commonly due to the emergence of a secondary mutation (T790M) in EGFR (in 50% of cases), amplification of the genes encoding the ERBB2 and MET receptor tyrosine kinases in 12 and 5% of cases, respectively, and phenotypic transformation of the adenocarcinomas to small cell lung cancer (5% of cases). Previously, in an effort to develop strategies to overcome T790M-mediated resistance, we generated tetracycline-inducible transgenic mice that express the EGFRL858R+T790M in the lung epithelium. Upon administration of doxycycline these mice develop lung adenocarcinomas that are resistant to TKIs. However, the combination of the irreversible TKI afatinib and the EGFR antibody cetuximab showed dramatic responses in these transgenic mice. These preclinical studies led to a clinical trial of these agents, which has showing a promising 30% response rate in patients with EGFR mutant tumors resistant to TKIs. However, tumors also acquire resistance to this drug combination and the mechanisms of resistance to afatinib+cetuximab are currently unknown. We set out to identify these mechanisms using xenograft and transgenic mouse models of EGFR mutant lung cancer. Transgenic mice with EGFRL858R+T790M-induced tumors were treated with afatinib+cetuximab using an intermittent dosing strategy that we had previously used to generate erlotinib-resistant tumors in mice with EGFRL858R and EGFRDEL-induced tumors. 75% of mice develop afatinib+cetuximab resistant tumors after three month-long rounds of treatment. The same treatment strategy applied to xenografts harboring subcutaneous tumors induced by EGFRDEL+T790M gave rise to resistant tumors in 20% of cases. Analysis of the afatinib+cetuximab resistant tumors performed to date has not revealed additional mutations in the EGFR transgene, the ERBB2 kinase domain or KRAS. Additional sequencing studies and examination of signaling pathway alterations in the resistant tumors are ongoing. Uncovering mechanisms of resistance to this drug combination will allow the development of strategies to treat tumors that acquire resistance to EGFR-directed therapies. Citation Format: Valentina Pirazzoli, Elisa de Stanchina, Jungfeng Xia, Zhongming Zhao, William Pao, Katerina A. Politi. Modeling acquired resistance to EGFR-directed therapies in mouse models of lung cancer. [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 933. doi:10.1158/1538-7445.AM2013-933 |
Databáze: | OpenAIRE |
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