Abstract 1916: β3 integrin/KRAS/RalB complex drives tumor stemness and resistance to EGFR inhibition

Integrin αvβ3 expression is a marker of tumor progression for a wide range of histologically distinct cancers, yet the molecular mechanism by which αvβ3 influences the growth and malignancy of cancer is poorly understood. Here, we reveal that integrin αvβ3, in the unligated state on lung, breast and pancreatic cancer cells, recruits KRAS and RalB to the plasma membrane, leading to the activation of TBK-1/c-Rel. These events are both necessary and sufficient to promote tumor initiation, anchorage-independence, self-renewal, as well as resistance to nutrient deprivation and treatment with receptor tyrosine kinase (RTK) inhibitors such as erlotinib. Genetic or pharmacological inhibition of RalB or its effectors suppress tumor initiation, self-renewal, and re-sensitizes tumors to RTK inhibition. These findings not only identify ανβ3 as a marker/driver of tumor stemness but also provide a strategy to overcome tumor resistance to RTK Inhibition. Citation Format: Laetitia Jocelyne Seguin, Shumei Kato, Aleksandra Franovic, Maria Fernanda Camargo, Katrhyn Elliott, Mayra Yebra, Jacqueline Lesperance, Ainhoa Mielgo, Jay Desgrosellier, Sudarshan Anand, Sara Weis, David Cheresh. β3 integrin/KRAS/RalB complex drives tumor stemness and resistance to EGFR inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1916. doi:10.1158/1538-7445.AM2014-1916