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oai:docta.ucm.es:20.500.14352/935592025-03-18T12:36:34Zcom_20.500.14352_14col_20.500.14352_15

Functional role and therapeutic targeting of p21-activated kinase 4 in multiple myeloma Fulciniti, Mariateresa Martínez López, Joaquín Senapedis, William Oliva, Stefania Bandi, Rajya Lakshmi Amodio, Nicola Xu, Yan Szalat, Raphael Gulla, Annamaria Samur, Mehmet K. Roccaro, Aldo Linares Gómez, María Cea, Michele Baloglu, Erkan Argueta, Christian Landesman, Yosef Shacham, Sharon Liu, Siyuan Schenone, Monica Wu, Shiaw-Lin Karger, Barry Prabhala, Rao Anderson, Kenneth C. Munshi, Nikhil C. Ciencias Biomédicas 24 Ciencias de la Vida Dysregulated oncogenic serine/threonine kinases play a pathological role in diverse forms of malignancies, including multiple myeloma (MM), and thus represent potential therapeutic targets. Here, we evaluated the biological and functional role of p21-activated kinase 4 (PAK4) and its potential as a new target in MM for clinical applications. PAK4 promoted MM cell growth and survival via activation of MM survival signaling pathways, including the MEK-extracellular signal-regulated kinase pathway. Furthermore, treatment with orally bioavailable PAK4 allosteric modulator (KPT-9274) significantly impacted MM cell growth and survival in a large panel of MM cell lines and primary MM cells alone and in the presence of bone marrow microenvironment. Intriguingly, we have identified FGFR3 as a novel binding partner of PAK4 and observed significant activity of KPT-9274 against t(4;14)-positive MM cells. This set of data supports PAK4 as an oncogene in myeloma and provide the rationale for the clinical evaluation of PAK4 modulator in myeloma. Ron and Anita Wornick Fund National Institutes of Health National Cancer Institute Department of Veterans Affairs Merit Review Centro Nacional de Investigaciones Oncológicas (España) Depto. de Bioquímica y Biología Molecular Fac. de Farmacia TRUE pub 2024-01-17T10:30:43Z 2024-01-17T10:30:43Z 2017 journal article VoR https://hdl.handle.net/20.500.14352/93559 0006-4971 10.1182/blood-2016-06-724831 1528-0020 eng info:eu-repo/grantAgreement/PO1-155258 info:eu-repo/grantAgreement/P50-100707 info:eu-repo/grantAgreement/I01BX001584-01 info:eu-repo/grantAgreement/BA15/00035 Fulciniti M, Martinez-Lopez J, Senapedis W, Oliva S, Lakshmi Bandi R, Amodio N, et al. Functional role and therapeutic targeting of p21-activated kinase 4 in multiple myeloma. Blood 2017;129:2233–45. https://doi.org/10.1182/blood-2016-06-724831. open access application/pdf American Society of Hematology