Integrin ?v?3 is expressed in the most aggressive and metastatic cancers. Here, new experimental data suggests that ?v?3 also drives a novel pathway of resistance to EGFR-targeted therapies. In fact, different epithelial carcinoma cell lines exposed to the EGFR inhibitors erlotinib or lapatinib for several weeks show enhanced expression of the integrin ?3 subunit in the subpopulation of surviving cells. Mechanistically, ?v?3 integrin promotes the plasma membrane clustering of oncogenic K-Ras to drive its signaling to RalB and its downstream effectors. This ?v?3/K-Ras/RalB "oncogenic unit" not only increases anchorage-independence in vitro and tumor growth in vivo, but it also renders tumors resistant to EGFR inhibition. These findings suggest that disabling components of this novel pathway may enhance the sensitivity to EGFR-targeted therapies. Experiments outlined in this proposal will examine the significance of the ?v?3/K-Ras interaction in terms of EGFR inhibitor resistance for a number of epithelial cancers in vitro and in vivo. The goal of Aim 1 is o define the structural basis for the association between integrin ?v?3 and K-Ras, which appears to drive RalB- mediated signaling in epithelial carcinoma cells. Studies in Aim 2 are designed to determine which ?3/K- Ras/RalB effectors drive anchorage-independence and erlotinib resistance, and to test both genetic and pharmacological strategies to block this pathway in vitro. Finally, Aim 3 will evaluate strategies to overcome EGFR inhibitor resistance for subcutaneous and orthotopic mouse cancer models. If successful, these studies will support the continued use of EGFR-targeted therapies in the clinic, and offer novel strategies to improve response to such therapies once tumors acquire resistance.

Public Health Relevance

Although a number of EGF receptor inhibitors are approved to treat various epithelial cancers, de novo and acquired resistance mechanisms are common and limit the use of these drugs. We have identified a novel pathway in which integrin ?v?3 expressed by a variety of epithelial cancers not only represents a marker of EGFR inhibitor resistance but does so by coupling to and activating K-Ras/RalB. Understanding the mechanism by which ?v?3 drives EGFR inhibitor resistance will allow us to develop novel strategies to sensitize a range of tumors to EGFR-targeted therapies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Woodhouse, Elizabeth
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University of California San Diego
Schools of Medicine
La Jolla
United States
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