Investigation of Aurora A kinase as a potential therapeutic target in K-Ras-induced lung cancer.

Abstract

Lung cancer is the leading cause of cancer mortality worldwide. The most frequent genetic changes found in lung cancer are activating point mutations in the K-Ras gene. Although K-Ras mutations have been causally linked to the oncogenic process, different approaches to target K-Ras for therapy have been unsuccessful. Therefore, in order to select better targets for lung cancer therapy, the key cancer-relevant K-Ras downstream pathways will need to be identified. The overall objective of this application is to identify novel therapeutic targets in K-Ras-mediated lung cancer. The central hypothesis of this application is that (1) oncogenic K-Ras activates the mitotic kinase Aurora A and (2) that Aurora A is a relevant therapeutic target in K-Ras-induced lung cancer. This hypothesis was formulated on the basis of previous studies showing that Aurora A directly phosphorylates Ras effector pathway components, that Aurora A cooperates with Ras to induce malignant transformation, and that pharmacological inhibition of Aurora A activity in human cancer cells (some of those positive for K-Ras mutations) impairs malignant behavior. In order to test this hypothesis, we will pursue the following specific aims: (1) determine how induction or inhibition of oncogenic K-Ras expression in human lung cancer cells affects Aurora A kinase expression and activity; and (2) determine how inhibition of Aurora A expression in human K-Ras positive lung cancer cells affects the oncogenic phenotype. Our contribution is expected to be the identification of downstream targets of K-Ras in the lung that not only contribute to the oncogenic process, but also that are therapeutically relevant. This contribution is significant, because it is expected to provide the knowledge needed to develop novel pharmacologic strategies that will improve therapeutic outcome for lung cancer patients. The rationale that underlies the proposed research program is that it is expected to yield important new insights into the molecular oncogenic mechanisms triggered by K-Ras in lung cancer, while, at the same time, it is expected to provide experimental validation for the development of new target-directed pharmacological agents to treat K-Ras-induced lung cancer.