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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA045726-26A1
Application #
8438098
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Woodhouse, Elizabeth
Project Start
1988-04-01
Project End
2018-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
26
Fiscal Year
2013
Total Cost
$350,731
Indirect Cost
$124,453
Name
University of California San Diego
Department
Pathology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Cosset, Érika; Ilmjärv, Sten; Dutoit, Valérie et al. (2017) Glut3 Addiction Is a Druggable Vulnerability for a Molecularly Defined Subpopulation of Glioblastoma. Cancer Cell 32:856-868.e5
Seguin, Laetitia; Desgrosellier, Jay S; Weis, Sara M et al. (2015) Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol 25:234-40
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Seguin, Laetitia; Kato, Shumei; Franovic, Aleksandra et al. (2014) An integrin ??-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. Nat Cell Biol 16:457-68
Cheresh, David A; Stupack, Dwayne G (2014) Tumor angiogenesis: putting a value on plastic GEMMs. Circ Res 114:9-11
Seguin, Laetitia; Gozo, Maricel; Weis, Sara M et al. (2014) Targeting the Achilles' heel of drug-resistant cancer stem cells. Cell Cycle 13:2017-8
Desgrosellier, Jay S; Lesperance, Jacqueline; Seguin, Laetitia et al. (2014) Integrin ?v?3 drives slug activation and stemness in the pregnant and neoplastic mammary gland. Dev Cell 30:295-308
Lau, Steven K M; Shields, David J; Murphy, Eric A et al. (2012) EGFR-mediated carcinoma cell metastasis mediated by integrin ?v?5 depends on activation of c-Src and cleavage of MUC1. PLoS One 7:e36753
Huang, M; Anand, S; Murphy, E A et al. (2012) EGFR-dependent pancreatic carcinoma cell metastasis through Rap1 activation. Oncogene 31:2783-93

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