| While EGFR inhibitors have been largely successful in treating lung adenocarcinomas harboring EGFR mutations, the formation of resistance to such inhibitors represents the next hurdle in progressing toward a sustainable cure in this population of cancer patients. The most observed mechanism of acquired resistance in this population is the emergence of T790M mutations in the EGFR gene. Our preliminary data suggest that the MAPK pathway is required for cell survival in EGFR-dependent NSCLC cell lines, including those harboring the T790M lesion. Therefore, targeting both MAPK and EGFR could have synergistic activity in EGFR-dependent NSCLC. Although a number of MAPK inhibitors have been tested in clinical trials, they have not, to our knowledge, been tested concomitantly with erlotinib in a patient population which is likely to harbor EGFR-driven tumors. The purpose of this proposal is to develop supporting data for the initiation of such a clinical trial that tests whether MEK inhibition could augment EGFR-TKI activity. Furthermore, the MAPK module is also responsive to activation of MET, the amplification of which has also been linked to acquired resistance to EGFR inhibitors. Although mutations in K-ras and occasionally in Raf are detected in NSCLC, mutations in MEK or ERK have not been frequently identified in NSCLC tumors, suggesting that tumors may be less likely to develop mutations in this pathway that will result in acquired resistance to MEK inhibitors. We hypothesize that targeting EGFR-dependent tumors by dual inhibition of EGFR and the downstream MEK cascade will improve response rates and minimize acquired secondary resistance in EGFR-dependent NSCLC.
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