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Small molecule inhibition of group I p21-activated kinases in breast cancer induces apoptosis and potentiates the activity of microtubule stabilizing agents.
Ong, Christy C; Gierke, Sarah; Pitt, Cameron; Sagolla, Meredith; Cheng, Christine K; Zhou, Wei; Jubb, Adrian M; Strickland, Laura; Schmidt, Maike; Duron, Sergio G; Campbell, David A; Zheng, Wei; Dehdashti, Seameen; Shen, Min; Yang, Nora; Behnke, Mark L; Huang, Wenwei; McKew, John C; Chernoff, Jonathan; Forrest, William F; Haverty, Peter M; Chin, Suet-Feung; Rakha, Emad A; Green, Andrew R; Ellis, Ian O; Caldas, Carlos; O'Brien, Thomas; Friedman, Lori S; Koeppen, Hartmut; Rudolph, Joachim; Hoeflich, Klaus P.
Afiliación
  • Ong CC; Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA. ong.christy@gene.com.
  • Gierke S; Department of Pathology, Genentech, Inc., South San Francisco, CA, USA. gierke.sarah@gene.com.
  • Pitt C; Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA. cameron.pitt@ucsf.edu.
  • Sagolla M; New address: University of California, San Francisco, CA, USA. cameron.pitt@ucsf.edu.
  • Cheng CK; Department of Pathology, Genentech, Inc., South San Francisco, CA, USA. sagolla.meredith@gene.com.
  • Zhou W; Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA. ccheng@cal.berkeley.edu.
  • Jubb AM; Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA. zhou.wei@gene.com.
  • Strickland L; Department of Pathology, Genentech, Inc., South San Francisco, CA, USA. jubb.adrian@gene.com.
  • Schmidt M; Department of Diagnostics, Genentech, Inc., South San Francisco, CA, USA. sanders.laura@gene.com.
  • Duron SG; Department of Diagnostics, Genentech, Inc., South San Francisco, CA, USA. schmidt.maike@gene.com.
  • Campbell DA; Afraxis, La Jolla, CA, USA. sduron@coipharma.com.
  • Zheng W; New address: COI Pharmaceuticals, La Jolla, CA, USA. sduron@coipharma.com.
  • Dehdashti S; Afraxis, La Jolla, CA, USA. dcampbell@coipharma.com.
  • Shen M; New address: COI Pharmaceuticals, La Jolla, CA, USA. dcampbell@coipharma.com.
  • Yang N; National Center for Advancing Translational Sciences, Bethesda, MD, USA. wzheng@mail.nih.gov.
  • Behnke ML; National Center for Advancing Translational Sciences, Bethesda, MD, USA. seameen.dehdashti@fda.hhs.gov.
  • Huang W; New address: Food and Drug Administration, Silver Spring, MD, USA. seameen.dehdashti@fda.hhs.gov.
  • McKew JC; National Center for Advancing Translational Sciences, Bethesda, MD, USA. shenmin@mail.nih.gov.
  • Chernoff J; National Center for Advancing Translational Sciences, Bethesda, MD, USA. na.yang@nih.gov.
  • Forrest WF; National Center for Advancing Translational Sciences, Bethesda, MD, USA. mark.behnke@nih.gov.
  • Haverty PM; National Center for Advancing Translational Sciences, Bethesda, MD, USA. huangwe@mail.nih.gov.
  • Chin SF; National Center for Advancing Translational Sciences, Bethesda, MD, USA. john.mckew@gmail.com.
  • Rakha EA; New address: aTyr Pharma, San Diego, CA, USA. john.mckew@gmail.com.
  • Green AR; Fox Chase Cancer Center, Philadelphia, PA, USA. Jonathan.Chernoff@fccc.edu.
  • Ellis IO; Department of Biostatistics, Genentech, Inc., South San Francisco, CA, USA. forrest.bill@gene.com.
  • Caldas C; Department of Bioinformatics, Genentech, Inc., South San Francisco, CA, USA. haverty.peter@gene.com.
  • O'Brien T; Cancer Research UK, University of Cambridge, Cambridge, UK. Suet-Feung.Chin@cruk.cam.ac.uk.
  • Friedman LS; Histopathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospitals, Nottingham, UK. emadrakha@yahoo.com.
  • Koeppen H; Histopathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospitals, Nottingham, UK. Andrew.Green@nottingham.ac.uk.
  • Rudolph J; Histopathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospitals, Nottingham, UK. Ian.Ellis@nottingham.ac.uk.
  • Hoeflich KP; Cancer Research UK, University of Cambridge, Cambridge, UK. Carlos.Caldas@cruk.cam.ac.uk.
Breast Cancer Res ; 17: 59, 2015 Apr 23.
Article en En | MEDLINE | ID: mdl-25902869
INTRODUCTION: Breast cancer, the most common cause of cancer-related deaths worldwide among women, is a molecularly and clinically heterogeneous disease. Extensive genetic and epigenetic profiling of breast tumors has recently revealed novel putative driver genes, including p21-activated kinase (PAK)1. PAK1 is a serine/threonine kinase downstream of small GTP-binding proteins, Rac1 and Cdc42, and is an integral component of growth factor signaling networks and cellular functions fundamental to tumorigenesis. METHODS: PAK1 dysregulation (copy number gain, mRNA and protein expression) was evaluated in two cohorts of breast cancer tissues (n=980 and 1,108). A novel small molecule inhibitor, FRAX1036, and RNA interference were used to examine PAK1 loss of function and combination with docetaxel in vitro. Mechanism of action for the therapeutic combination, both cellular and molecular, was assessed via time-lapse microscopy and immunoblotting. RESULTS: We demonstrate that focal genomic amplification and overexpression of PAK1 are associated with poor clinical outcome in the luminal subtype of breast cancer (P=1.29×10(-4) and P=0.015, respectively). Given the role for PAK1 in regulating cytoskeletal organization, we hypothesized that combination of PAK1 inhibition with taxane treatment could be combined to further interfere with microtubule dynamics and cell survival. Consistent with this, administration of docetaxel with either a novel small molecule inhibitor of group I PAKs, FRAX1036, or PAK1 small interfering RNA oligonucleotides dramatically altered signaling to cytoskeletal-associated proteins, such as stathmin, and induced microtubule disorganization and cellular apoptosis. Live-cell imaging revealed that the duration of mitotic arrest mediated by docetaxel was significantly reduced in the presence of FRAX1036, and this was associated with increased kinetics of apoptosis. CONCLUSIONS: Taken together, these findings further support PAK1 as a potential target in breast cancer and suggest combination with taxanes as a viable strategy to increase anti-tumor efficacy.
Asunto(s)

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Apoptosis / Inhibidores de Proteínas Quinasas / Moduladores de Tubulina / Quinasas p21 Activadas / Microtúbulos Tipo de estudio: Prognostic_studies Idioma: En Revista: Breast Cancer Res Asunto de la revista: NEOPLASIAS Año: 2015 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Apoptosis / Inhibidores de Proteínas Quinasas / Moduladores de Tubulina / Quinasas p21 Activadas / Microtúbulos Tipo de estudio: Prognostic_studies Idioma: En Revista: Breast Cancer Res Asunto de la revista: NEOPLASIAS Año: 2015 Tipo del documento: Article