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New Agents and Approaches for Targeting the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR Cell Survival Pathways

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Cell Death Signaling in Cancer Biology and Treatment

Part of the book series: Cell Death in Biology and Diseases ((CELLDEATH))

Abstract

The Ras/Raf/MEK/ERK and PI3K/Akt/mTOR cascades are often activated by genetic alterations, either by mutations in upstream signaling molecules or by mutations in intrinsic pathway components. Upstream mutations in one signaling pathway or even in downstream components of the same pathway can alter the sensitivity of the cells to certain small molecule inhibitors. These pathways have profound effects on proliferative, apoptotic, and differentiation pathways. Dysregulation of components of these pathways can contribute to: malignant transformation, resistance to other pathway inhibitors, and chemotherapeutic drug resistance. This chapter will first briefly describe these pathways and then evaluate potential uses of Raf, MEK, PI3K, Akt, and mTOR inhibitors that have been investigated in preclinical and clinical investigations.

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Acknowledgments

MC and GM were supported in part by grants from the Italian “Ministero dell’Istruzione, dell’Università e della Ricerca (Ministry for Education, Universities and Research)—MIUR” PRIN 2008 and FIRB-MERIT n. RBNE08YYBM. MC was also supported in part by a grant to the CNR from the Italian Ministry of Economy and Finance for the Project FaReBio di Qualità. ML was supported in part by a grant from the Italian Ministry of Health, Ricerca Finalizzata Stemness 2008 entitled “Molecular Determinants of Stemness and Mesenchymal Phenotype in Breast Cancer”. AMM was supported in part by grants from Fondazione del Monte di Bologna e Ravenna, MinSan 2008 “Molecular therapy in pediatric sarcomas and leukemias against IGF-IR system: new drugs, best drug–drug interactions, mechanisms of resistance and indicators of efficacy”, MIUR PRIN 2008 (2008THTNLC), and MIUR FIRB 2010 (RBAP10447J-003) and 2011 (RBAP11ZJFA_001). MM was supported in part from the Italian Association for Cancer Research (AIRC), the Cariplo Foundation, and the Italian Ministry of Health. AT was supported in part by grants from the Italian “Ministero dell’Istruzione, dell’Università e della Ricerca (Ministry for Education, University and Research) —MIUR—PRIN 2008 and grant from “Sapienza”, University of Rome 2009–11.

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  1. Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA

    James A. McCubrey, Linda S. Steelman, William H. Chappell, Stephen L. Abrams & Richard A. Franklin

  2. Department of Internal Medicine and Specialties University of Palermo, Palermo, Italy

    Giuseppe Montalto

  3. Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare “Alberto Monroy”, Palermo, Italy

    Melchiorre Cervello

  4. Department of Biomedical Sciences, University of Catania, Catania, Italy

    Ferdinando Nicoletti, Graziella Malaponte, Clorinda Massarino & Massimo Libra

  5. Department of Medicine, University of Göttingen, Göttingen, Germany

    Jörg Bäsecke

  6. Sapienza, University of Rome, Department of Cellular Biotechnology and Hematology, Rome, Italy

    Agostino Tafuri

  7. Regina Elena National Cancer Institute, Rome, Italy

    Michele Milella

  8. Institute of Molecular Genetics, National Research Council-Rizzoli Orthopedic Institute, Bologna, Italy

    Francesca Chiarini, Camilla Evangelisti & Alberto M. Martelli

  9. Department of Biomedical and Neuromotor Sciences, Università di Bologna, Bologna, Italy

    Lucio Cocco & Alberto M. Martelli

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    Daniel E. Johnson

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McCubrey, J.A. et al. (2013). New Agents and Approaches for Targeting the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR Cell Survival Pathways. In: Johnson, D. (eds) Cell Death Signaling in Cancer Biology and Treatment. Cell Death in Biology and Diseases. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-5847-0_13

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