Abstract CN06-03: Cell plasticity promotes drug resistance and pathway redundancy.

Abstract

Abstract Multiple signal transduction pathways can be concurrently active within a single cell, and extensive crosstalk can occur between RTKs. Additionally, tumor tissues can be comprised of a heterogeneous collection of cell states utilizing distinct RTKs for maintenance of tumor cell growth and survival. As a consequence of this complexity, many tumors may be only partially sensitive to single agent therapies and would require the interdiction of multiple RTKs and other protein signaling targets for optimal anticancer therapy. Understanding pathway crosstalk is vital to guide the rational combination of approved and experimental anticancer agents. Resistance to targeted therapies can result from de novo pathway redundancy, from acquired feedback activation of parallel pathways and from de novo or acquired cell plasticity. It is clear that metastatic cancers are increasingly heterogeneous, that is many different cell types and states are present within cancer tissues, and importantly metastatic cancers show increased resistance to radiation, chemotherapies, and targeted therapies. Cellular plasticity in epithelial cancers has been associated with progression and resistant to anticancer therapies. Several forms of plasticity have been documented, including epithelial mesenchymal transition (EMT), endothelial-mesenchymal transition, and neuroendocrine-epithelial transition. Epithelial mesenchymal transition (EMT) is an important cellular change promoting metastatic cell survival. We have shown mesenchymal-like tumors are relatively resistant to EGFR-TKi (Thomson, Cancer Res 2005), to IGF1R TKi (Buck, Cancer Res 2008), and to a broad spectrum of chemotherapy agents. A similar resistance of EMT-derived cells to anticancer therapies has been shown clinically in breast cancer patients (Creighton PNAS 2009), in prostate cancers (Domingo-Domenech, Cancer Cell 2012), and in NSCLC patients (Sequist, Cancer Cell 2012). Finally clinical EMT biomarkers predict response to EGFR inhibitors in NSCLC patients (Yauch, Clin. Cancer Res 2005; Byers et al., Clin Cancer Res 2012). New therapeutics are needed to target the new spectrum of tumor survival signals now present within EMT-derived cells and within related cancer-stem cells Through the generation and molecular characterization of EMT models, coupled with RNAi-based target validation studies and follow-on pharmacology studies, new targets and compounds which promote death of metastatic cells can be identified and validated in panels of cell lines and in animal models. Cell models for in vitro and in vivo target progression will broadly reflect both inducible and epigenetically-fixed mesenchymal cell states. In two cases (H358 and A549), TGFbeta was used to induce a reversible metastable mesenchymal cell state. The role of TGFbeta as both tumor suppressor and promoter of metastatic progression highlight the altered signal transduction cascades downstream of TGFbeta receptor activation in comparing epithelial and mesenchymal cell states. Here we show that mesenchymal-like tumor cells derived by EMT are preferentially sensitive to perturbations in integrin, focal adhesion and MAPK signaling pathways. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN06-03. Citation Format: John D. Haley. Cell plasticity promotes drug resistance and pathway redundancy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN06-03.