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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
Status | Finished |
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Effective start/end date | 12/1/08 → 11/30/10 |
Funding
- Joans Legacy Lung Cancer Foundation: $100,000.00
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