Non-small cell lung cancer is a leading cause of death worldwide with an overall survival rate of less than 15% despite the use of aggressive therapies that often adversely impact the quality of life. Therefore, there is an urgent need for novel and effective treatment options for this devastating disease.

Cancer cells contain myriads of genetic mutations that not only determine their cancerous behavior, but also determine their response to cancer therapy. Indeed, certain cancer cells contain mutations that cause their dependency on specific rate-limiting cellular networks. This evidence has provided the rationale for the generation of novel drugs that target cancer-specific mutations. The success of this strategy is illustrated by the development of EGFR inhibitors in lung cancer therapy.

However, therapies that target networks specifically required for the survival of cancer cells are available only for a minority of lung cancer patients due to our incomplete understanding of the mechanisms required for tumor maintenance.

In this proposal, we will move toward the goal of identifying cellular networks that when inhibited cause the death of non-small cell lung cancer cells. We will focus our efforts on non-small cell lung cancer, the most prevalent form of this disease, using a multifaceted approach that takes advantage of cellular and mouse cancer models.

About 25% of non-small cell lung cancer cells contain activating mutations of the K-RAS protooncogene. These mutations give rise to oncogenic K-RAS, an activated form of K-RAS that stimulates the growth of cancer cells. Non-small cell lung cancer cells expressing oncogenic K-RAS often contain mutations that inactivate the INK4a/ARF or p53 genes. These genes oppose cancer formation (i.e., they are tumor suppressor genes) induced by oncogenic K-RAS and their loss is associated with aggressive lung cancer, poor prognosis, and resistance to therapy.

To identify novel targets for the development of rational therapies for lung cancer, we performed a genetic screening to identify genes that when inhibited cause the death of non-small cell lung cancer cells expressing oncogenic K-RAS and deficient for either INK4a/ARF or the p53 tumor suppressor.

We have determined that inhibition of focal adhesion kinase (FAK) causes cell death in non-small cell lung cancer cells expressing oncogenic K-RAS and deficient for either INK4a or p53, but not in lung cancer cells carrying other mutations. Furthermore, we have demonstrated that pharmacologic inhibition of FAK causes complete regression of non-small cell lung cancer expressing oncogenic K-RAS in transgenic mouse models of lung cancer.

Our experiments lead to the conclusion that FAK is required for maintaining the viability of non-small cell lung cancer cells expressing oncogenic K-RAS and deficient for either INK4a/ARF or p53. In this application, we propose to conclusively prove this hypothesis with a combination of experiments performed with cells derived from non-small cell lung cancer, faithful mouse models of non-small cell lung cancer, and clinical-grade pharmacologic inhibitors of FAK.

We propose that this research project is of clinical significance for several reasons. Our findings identify a novel therapeutic strategy for non-small cell lung cancer expressing oncogenic K-RAS and deficient for either the INK4a/ARF or p53 tumor suppressors. This is a notoriously aggressive type of lung cancer for which effective medical therapies do not exist. This subtype of non-small lung cancer occurs in about 15% of non-small cell lung cancer patients (about 20,000 cases per year in the United States). This is a significant number of patients with poor prognosis in dire need of effective cancer treatments.

Several inhibitors of FAK have been found to be non-toxic in early clinical trials in cancer patients. However, it has not been defined yet which cancer types will benefit from the use of FAK inhibitors. Our preliminary data predict that the oncogenic K-RAS/INK4a or p53-deficient genotype represents a biomarker for selecting patients likely to benefit from this novel therapeutic intervention.

We anticipate that this research proposal will lead to the development of novel, genotype-specific, targeted cancer therapies for this devastating disease.