The success of molecularly targeted cancer therapy using tyrosine kinase inhibitors (TKIs) faces a number of difficult challenges. Foremost among these is the ability to identify subsets of different cancers that are uniquely sensitive to targeted agents, often identified by the presence of genetic markers implying """"""""dependence"""""""" or """"""""addiction"""""""" to the targeted pathway. Equally important to the longterm success of these therapies is understanding and circumventing acquired drug resistance, which is a key limitation to their clinical effectiveness. Acquired resistance to drugs targeting growth factor receptors differs from resistance to genotoxic cancer chemotherapy, and may include both specific mutations in targeted receptors, as well as more complex functional alterations in signaling networks. Here we will use non-small cell lung cancer (NSCLC) cell line models that appear to faithfully recapitulate key signaling dependence of cancers with activating mutations in the Epidermal Growth Factor Receptor (EGFR) gene, identifying a subset of lung cancers with extreme sensitivity to EGFR TKIs. We outline three aims that address the acquisition of resistance in tumors that were previously sensitive to these agents:
in Aim 1, we will generate cell line models for acquired resistance to """"""""second generation"""""""" irreversible inhibitors of EGFR, and use genetic, signaling and functional analyses to dissect the underlying mechanisms.
In Aim 2, we will use a high throughput shRNA screen of tyrosine kinases to identify candidate targets whose suppression may circumvent resistance to EGFR inhibitors.
In Aim 3, we will use lentiviral knockdown/reconstitution experiments to quantitate oncogene dependence of drug resistant cells, both on the initiating EGFR mutation and on associated signaling pathways that contribute to acquired drug resistance. Together, these aims will provide important insight into critical mechanisms that underlie the acquisition of resistance to novel inhibitors targeting growth factor receptors in human cancer.

Public Health Relevance

Understanding the mechanisms by which cancers that are sensitive to the new classes of targeted cancer therapies become resistant to these is critical to their eventual clinical success. Our approach is designed to dissect the molecular basis of resistance to these cancer drugs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129933-03
Application #
7780378
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Song, Min-Kyung H
Project Start
2008-04-01
Project End
2013-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
3
Fiscal Year
2010
Total Cost
$367,275
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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