Targeting 14-3-3-Mediated Survival

Emory University, Atlanta GA

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Abstract

14-3-3 proteins are phosphoserine/threonine-binding molecules that interact with many regulatory[unreadable] proteins critical for cell death and survival. Recent research has established 14-3-3 proteins as critical[unreadable] regulators of survival signaling network in many cell types. Clinical evaluations have revealed 14-3-3[unreadable] expression as an important prognostic parameter for poor survival in colorectal and pancreatic cancer[unreadable] patients. However, whether 14-3-3-mediated signaling pathway is essential for lung cancer survival, whether[unreadable] inhibition of the 14-3-3 prosurvival function can alter lung cancer cell sensitivity to chemotherapeutic agents,[unreadable] and whether 14-3-3 isoforms have any prognostic value for lung cancer patients remain unknown. Our[unreadable] proposal aims to translate the basic understanding into clinical gains for enhancing the therapeutic efficacy in[unreadable] lung cancer, as a component of an integrated P01 program project. We will test the hypothesis that 14-3-3[unreadable] supports survival of lung cancer cells by suppressing the proapoptotic activity of its associated proteins. We[unreadable] will specifically test whether disruption of 14-3-3/ligand interactions predisposes lung cancer cells to[unreadable] apoptosis and whether 14-3-3 inhibitors sensitize lung cancer cells to chemotherapeutic agents such as[unreadable] mTOR and microtubule inhibitors. Further, we will examine whether expression of 14-3-3 isoforms has any[unreadable] prognostic value for lung cancer patient survival and whether 14-3-3 isoform expression in lung cancer[unreadable] patients is a predictive marker for therapeutic response. Disruption of 14-3-3/ligand interactions may provide[unreadable] a novel strategy to block upregulated survival signaling in lung cancer cells, thus limiting clonal expansion[unreadable] and reversing resistance to cancer therapies. Isolation of small molecule inhibitors of 14-3-3 together with[unreadable] our mechanistic investigations may lead to development of an entirely new class of potential anticancer[unreadable] agents which will impact multiple signaling pathways in a fashion similar to HSP90 inhibitors. In addition, the[unreadable] frequency of 14-3-3 abnormalities will be prospectively established for the field of cancer drug development