Over 70% of patients whose lung cancers harbor specific mutations within the exons encoding the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) experience radiographic responses to the selective EGFR tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or erlotinib (Tarceva). However, after about one year, these patients develop progression of disease. No targeted therapy has proven clinically effective in treating acquired resistance. In the previously funded period, we identified several mechanisms of acquired resistance, including second-site EGFR mutations (>50% of cases) and amplification of the gene encoding the MET tyrosine kinase (up to 20% of cases). Using mouse models of lung cancer that we generated and characterized, we also showed that the most common form of resistance, mediated by the EGFR T790M mutation, could be overcome by a novel combination of the second-generation EGFR TKI, afatinib (BIBW2992), and the anti-EGFR antibody, cetuximab. A Phase IB/II clinical trial of this combination in humans has now shown unprecedented activity in this patient cohort with a 36% (8 of 22) radiographic response rate. However, at least one patient on this combination has already developed progressive disease, and surprisingly, some tumors without T790M have also responded. The overall goals of this revised proposal are to use human tumor specimens and cell lines, genetically engineered and xenograft mouse models, and various molecular and biochemical techniques to gain further knowledge about the subset of EGFR mutant harboring lung cancers that develop acquired resistance to EGFR inhibition. An improved understanding of acquired resistance will hopefully allow us to treat/suppress the development of progressive disease and provide new insights into the biology of cancers driven by EGFR or other mutant receptor tyrosine kinases.

Public Health Relevance

A new clinical trial involving two targeted agents (afatinib plus cetuximab) was rationally designed based upon findings from our previous funding period and has now shown unprecedented anti-tumor activity in patients with acquired resistance to EGFR tyrosine kinase inhibitors in lung cancer. The goal of this grant is to gain further knowledge about the subset of EGFR mutant harboring lung cancers that develop acquired resistance to EGFR inhibition. An improved understanding of acquired resistance will hopefully allow us to treat/suppress the development of progressive disease and provide new insights into the biology of cancers driven by EGFR or other mutant receptor tyrosine kinases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA121210-08
Application #
8634034
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Timmer, William C
Project Start
2006-04-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
8
Fiscal Year
2014
Total Cost
$293,717
Indirect Cost
$90,100
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Machiela, Mitchell J; Zhou, Weiyin; Karlins, Eric et al. (2016) Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome. Nat Commun 7:11843
Johnson, Douglas B; Estrada, Monica V; Salgado, Roberto et al. (2016) Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy. Nat Commun 7:10582
Qiao, Huan; Lovly, Christine M (2016) Cracking the Code of Resistance across Multiple Lines of ALK Inhibitor Therapy in Lung Cancer. Cancer Discov 6:1084-1086
Lovly, Christine M (2015) Combating acquired resistance to tyrosine kinase inhibitors in lung cancer. Am Soc Clin Oncol Educ Book :e165-73

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