Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer Journal Article

Authors: Regales, L.; Gong, Y.; Shen, R.; de Stanchina, E.; Vivanco, I.; Goel, A.; Koutcher, J. A.; Spassova, M.; Ouerfelli, O.; Mellinghoff, I. K.; Zakowski, M. F.; Politi, K. A.; Pao, W.
Article Title: Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer
Abstract: EGFR is a major anticancer drug target in human epithelial tumors. One effective class of agents is the tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. These drugs induce dramatic responses in individuals with lung adenocarcinomas characterized by mutations in exons encoding the EGFR tyrosine kinase domain, but disease progression invariably occurs. A major reason for such acquired resistance is the outgrowth of tumor cells with additional TKI-resistant EGFR mutations. Here we used relevant transgenic mouse lung tumor models to evaluate strategies to overcome the most common EGFR TKI resistance mutation, T790M. We treated mice bearing tumors harboring EGFR mutations with a variety of anticancer agents, including a new irreversible EGFR TKI that is under development (BIBW-2992) and the EGFR-specific antibody cetuximab. Surprisingly, we found that only the combination of both agents together induced dramatic shrinkage of erlotinib-resistant tumors harboring the T790M mutation, because together they efficiently depleted both phosphorylated and total EGFR. We suggest that these studies have immediate therapeutic implications for lung cancer patients, as dual targeting with cetuximab and a second-generation EGFR TKI may be an effective strategy to overcome T790M-mediated drug resistance. Moreover, this approach could serve as an important model for targeting other receptor tyrosine kinases activated in human cancers.
Keywords: epidermal growth factor; controlled study; intercellular signaling peptides and proteins; unclassified drug; gene mutation; mutation; erlotinib; drug efficacy; nonhuman; antineoplastic agents; drug targeting; paclitaxel; animal cell; mouse; animals; mice; animal tissue; gene expression; gene expression profiling; tumor volume; lung neoplasms; epidermal growth factor receptor; animal experiment; animal model; lung cancer; receptor, epidermal growth factor; antineoplastic activity; tumor xenograft; drug resistance, neoplasm; tumor cells, cultured; cetuximab; cancer model; mice, transgenic; cancer resistance; protein tyrosine kinase inhibitor; protein kinase inhibitors; lung tumor; antibodies, monoclonal; lung adenocarcinoma; mice, nude; transplantation, heterologous; neoplasm transplantation; disease models, animal; quinazolines; pemetrexed; glycoproteins; phosphoprotein; amphiregulin; bibw 2992; epiregulin
Journal Title: Journal of Clinical Investigation
Volume: 119
Issue: 10
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2009-10-01
Start Page: 3000
End Page: 3010
Language: English
DOI: 10.1172/jci38746
PUBMED: 19759520
PROVIDER: scopus
PMCID: PMC2752070
Notes: --- - "Cited By (since 1996): 12" - "Export Date: 30 November 2010" - "CODEN: JCINA" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Ronglai Shen
    129 Shen
  2. Lucia Regales
    12 Regales
  3. William Pao
    141 Pao
  4. Maureen F Zakowski
    280 Zakowski
  5. Katerina A Politi
    23 Politi
  6. Jason A Koutcher
    236 Koutcher
  7. Yixuan Gong
    15 Gong
  8. Igor Vivanco
    12 Vivanco
  9. Aviva J Goel
    7 Goel