Gelardi, Teresa (2008) Development of two novel targeted agents as a strategy to overcome the resistance to EGFR inhibitors. [Tesi di dottorato] (Inedito)

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Abstract

Background. Therapeutic inhibition of a single transduction pathway is often inefficient due to activation of alternative signaling. The mammalian target of rapamycin (mTOR), Protein Kinase Cbeta (PKC2), Akt and VEGF are involved in proliferation, survival and angiogenic pathways and have been implicated in the resistance to EGFR inhibitors. Therefore, blocking these pathways to interfere at multiple levels with tumor growth may result in a more efficient therapeutic strategy. Materials and Methods. We used everolimus, an inhibitor of mTOR, and enzastaurin, an inhibitor of VEGF Receptor-dependent PKC2, alone or in combination with anti-EGFR drugs gefitinib or cetuximab, on human cancer cell lines sensitive and resistant to EGFR inhibitors, both in vitro and in vivo. Results. We demonstrated that everolimus and enzastaurin are active against resistant cancer cell lines and are able to restore the ability of EGFRinhibitors to inhibit growth and survival. Everolimus and enzastaurin reduce the expression of EGFR-related signaling effectors and VEGF production. In addition, everolimus inhibits proliferation and capillary tube formation of endothelial cells and this effect is enhanced in combination with gefitinib. Finally, both everolimus and enzastaurin, when used in combination with gefitinib, demonstrate a cooperative effect on gefitinib resistant colon cancer xenografts, and on activation of signaling proteins and VEGF secretion. Conclusions. Targeting important pathways for tumoral growth and angiogenesis with everolimus and enzastaurin overcomes resistance to EGFR inhibitors and produces a cooperative effect with these agents, providing a Valid therapeutic strategy to be tested in a clinical setting.

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