Dual Targeted Therapy - Can MEK Inhibition Improve Response and Reduce Acquired Resistance in EGFR-Dependent NSCLC

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LAY ABSTRACT Lung cancer is a devastating disease, both nationally and worldwide. In the US alone, approximately 190,000 new cases of lung cancer are diagnosed each year, and almost all afflicted patients ultimately succumb to the disease. Of all cancers, however, lung cancer is unique in that the primary etiology has been well established to be the result of a modifiable risk factor'(i.e. smoking). Unfortunately, -15,000 cases of lung cancer each year are not linked to smoking, the majority occurring in women. These tumors are frequently dependent upon a mutation in the epidermal growth factor receptor (EGFR) gene. As a testament to the dependence on EGFR, Tarceva is a drug that inhibits EGFR and has demonstrated unprecedented responses when utilized in this population, although response is short-lived. Patients frequently develop resistance to Tarceva and these events have plagued the clinical community. Other molecular strategies to prevent such resistance are needed to progress toward establishing an effective cure for EGFR-dependent lung cancers. Combination therapy directed at multiple targets is a strategy to maximize response and minimize resistance and has been widely used in traditional cancer therapy. Likewise, targeting multiple molecules in EGFR-dependent lung cancer may prevent common mechanisms of tumor resistance. Our preliminary data show that EGFR-dependent lung tumors use a particular strategy for induction of tumor growth and survival. Furthermore, lung cancer cell lines which exhibit resistance to Tarceva due to presence of a specific mutation EGFR, or perhaps mutation of another gene, retain sensitivity to inhibitors of signaling pathway downstream EGFR. Therefore, we plan to explore the hypothesis that using two different targeted inhibitors in EGFR-dependent NSCLC may offer significant advantages in prohibiting the formation of resistance to treatment. SCIENTIFIC ABSTRACT 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
Effective start/end date12/1/0811/30/10


  • Joans Legacy Lung Cancer Foundation: $100,000.00


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