| Mutations of the epidermal growth factor receptor (EGFR) gene are relatively uncommon among non-small cell lung cancer (NSCLC) patients. However, such mutations are observed with high frequency in a particular subset of NSCLC patients—women who have never smoked. The recent development of specific EGFR inhibitors has been highly beneficial to such, and about 75% of these individuals undergo initial response when treated with Iressa or Tarceva, the two most commonly used EGFR inhibitors. Mechanistic studies have revealed that tumors with EGFR mutations appear to require a higher level of EGFR activity than tumors with normal EGFR. Such tumors are said to be ‘addicted’ to EGFR, and the cells within these tumors die when EGFR function is inhibited. Unfortunately, many individuals with EGFR-addicted tumors ultimately relapse due to secondary mutations that cause EGFR to become resistant to the inhibitors. This unfortunate outcome emphasizes the need to learn more about how EGFR works, and figure out how to inhibit EGFR signaling downstream of the mutated receptor. Our preliminary data indicate that an enzyme called phospholipase D1 (PLD1) forms a nodal point of integration of EGFR signaling to downstream pathways that control proliferation, invasion, and survival. We have observed that inhibition of PLD1 results in death of EGFR-addicted cells, even those that are resistant to EGFR inhibitors. Our objective is to obtain pre-clinical proof-of-principle in support of the use of PLD1 inhibitors in the treatment of individuals whose tumors have EGFR mutations. We believe that such drugs, in combination with EGFR inhibitors, may have greater efficacy in treating EGFR-addicted lung cancer. Furthermore, PLD1 inhibitors should be effective in treating individuals who have acquired resistance to EGFR inhibitors. Our objectives are to confirm these hypothetical predictions and to develop models to test the efficacy of PLD1 inhibitor in future experiments.
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