The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib areeffective therapeutic agents for patients with non-small cell lung cancer (NSCLC) whose tumors harboractivating mutations in EGFR. Most, if not all, patients who initially develop a partial or complete response togefitinib or erlotinib will eventually develop progression of their cancer while taking these therapies. The onlyknown mechanism of resistance, a secondary mutation in EGFR itself (a substitution of methionine forthreonine at position 790, EGFR T790M) has been detected in approximately 50% of patients developingresistance to gefitinib or erlotinib. This finding has spurred the clinical development of irreversible EGFRinhibitors that can inhibit an EGFR T790M to treat cancers that have become resistant to gefitinib/erlotinib.To identify of mechanisms of acquired resistance to gefitinib or erlotinib, we have generated gefitinibresistantclones of EGFR mutant NSCLC cell lines by exposing them to increasing concentrations ofgefitinib. In previous work, we identified an EGFR T790M in vitro model of resistance, thereby demonstratingthat in vitro models can be used to discover resistance mechanisms observed in patients. These paired[parental and resistant clone) cell lines provide valuable preclinical models in which to systematicallydetermine mechanisms of gefitinib resistance and their in vitro sensitivity to novel therapeutic agents. Oncedentified, tumor specimens from EGFR mutant patients that have developed acquired resistance togefitinib/erlotinib will be assessed to determine if these resistance mechanisms can also be detected inaatients. Furthermore, based on the findings above, novel therapeutic combinations will be evaluated in thegefitinib-resistant cell line models with differing mechanisms of resistance. These studies will serves as thejasis for rationally designed clinical trials for patients with gefitinib/erlotinib resistance. These studies will beaccomplished through the following specific aims:
Aim 1 : To discover mechanisms of acquired resistance toEGFR-targeted agents.
Aim 2 : To determine whether targeting resistance mechanisms in vitro usingpharmacologic inhibitors or by RNA interference (RNAi) will lead to growth inhibition of resistant NSCLC cellines Aim 3:To design and conduct clinical studies in NSCLC patients with different mechanisms of acquiredresistance to gefitinib/erlotinib. Since EGFR TKIs are highly effective initial treatments for patients with EGFRmutant cancers, it will be critical to identify the how these cancers eventually become resistant. The studiesn this grant proposal will help develop the future treatments for patients with different mechanisms ofacquired resistance to EGFR TKIs.
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