2. Academic Validation
  3. Small molecule inhibition of group I p21-activated kinases in breast cancer induces apoptosis and potentiates the activity of microtubule stabilizing agents

Small molecule inhibition of group I p21-activated kinases in breast cancer induces apoptosis and potentiates the activity of microtubule stabilizing agents

  • Breast Cancer Res. 2015 Apr 23;17(1):59. doi: 10.1186/s13058-015-0564-5.
Christy C Ong 1,  Sarah Gierke 2,  Cameron Pitt 3 4,  Meredith Sagolla 5,  Christine K Cheng 6,  Wei Zhou 7,  Adrian M Jubb 8,  Laura Strickland 9,  Maike Schmidt 10,  Sergio G Duron 11 12,  David A Campbell 13 14,  Wei Zheng 15,  Seameen Dehdashti 16 17,  Min Shen 18,  Nora Yang 19,  Mark L Behnke 20,  Wenwei Huang 21,  John C McKew 22 23,  Jonathan Chernoff 24,  William F Forrest 25,  Peter M Haverty 26,  Suet-Feung Chin 27,  Emad A Rakha 28,  Andrew R Green 29,  Ian O Ellis 30,  Carlos Caldas 31,  Thomas O'Brien 32,  Lori S Friedman 33,  Hartmut Koeppen 34,  Joachim Rudolph 35,  Klaus P Hoeflich 36 37
Affiliations

Affiliations

  • 1 Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA. ong.christy@gene.com.
  • 2 Department of Pathology, Genentech, Inc., South San Francisco, CA, USA. gierke.sarah@gene.com.
  • 3 Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA. cameron.pitt@ucsf.edu.
  • 4 New address: University of California, San Francisco, CA, USA. cameron.pitt@ucsf.edu.
  • 5 Department of Pathology, Genentech, Inc., South San Francisco, CA, USA. sagolla.meredith@gene.com.
  • 6 Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA. ccheng@cal.berkeley.edu.
  • 7 Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA. zhou.wei@gene.com.
  • 8 Department of Pathology, Genentech, Inc., South San Francisco, CA, USA. jubb.adrian@gene.com.
  • 9 Department of Diagnostics, Genentech, Inc., South San Francisco, CA, USA. sanders.laura@gene.com.
  • 10 Department of Diagnostics, Genentech, Inc., South San Francisco, CA, USA. schmidt.maike@gene.com.
  • 11 Afraxis, La Jolla, CA, USA. sduron@coipharma.com.
  • 12 New address: COI Pharmaceuticals, La Jolla, CA, USA. sduron@coipharma.com.
  • 13 Afraxis, La Jolla, CA, USA. dcampbell@coipharma.com.
  • 14 New address: COI Pharmaceuticals, La Jolla, CA, USA. dcampbell@coipharma.com.
  • 15 National Center for Advancing Translational Sciences, Bethesda, MD, USA. wzheng@mail.nih.gov.
  • 16 National Center for Advancing Translational Sciences, Bethesda, MD, USA. seameen.dehdashti@fda.hhs.gov.
  • 17 New address: Food and Drug Administration, Silver Spring, MD, USA. seameen.dehdashti@fda.hhs.gov.
  • 18 National Center for Advancing Translational Sciences, Bethesda, MD, USA. shenmin@mail.nih.gov.
  • 19 National Center for Advancing Translational Sciences, Bethesda, MD, USA. na.yang@nih.gov.
  • 20 National Center for Advancing Translational Sciences, Bethesda, MD, USA. mark.behnke@nih.gov.
  • 21 National Center for Advancing Translational Sciences, Bethesda, MD, USA. huangwe@mail.nih.gov.
  • 22 National Center for Advancing Translational Sciences, Bethesda, MD, USA. john.mckew@gmail.com.
  • 23 New address: aTyr Pharma, San Diego, CA, USA. john.mckew@gmail.com.
  • 24 Fox Chase Cancer Center, Philadelphia, PA, USA. Jonathan.Chernoff@fccc.edu.
  • 25 Department of Biostatistics, Genentech, Inc., South San Francisco, CA, USA. forrest.bill@gene.com.
  • 26 Department of Bioinformatics, Genentech, Inc., South San Francisco, CA, USA. haverty.peter@gene.com.
  • 27 Cancer Research UK, University of Cambridge, Cambridge, UK. Suet-Feung.Chin@cruk.cam.ac.uk.
  • 28 Histopathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospitals, Nottingham, UK. emadrakha@yahoo.com.
  • 29 Histopathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospitals, Nottingham, UK. Andrew.Green@nottingham.ac.uk.
  • 30 Histopathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham and Nottingham University Hospitals, Nottingham, UK. Ian.Ellis@nottingham.ac.uk.
  • 31 Cancer Research UK, University of Cambridge, Cambridge, UK. Carlos.Caldas@cruk.cam.ac.uk.
  • 32 Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA. obrien.tom@gene.com.
  • 33 Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA. friedman.lori@gene.com.
  • 34 Department of Pathology, Genentech, Inc., South San Francisco, CA, USA. koeppen.hartmut@gene.com.
  • 35 Discovery Chemistry, Genentech, Inc., South San Francisco, CA, USA. rudolph.joachim@gene.com.
  • 36 Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA. klaushoeflich@hotmail.com.
  • 37 New address: Blueprint Medicines, Cambridge, MA, UK. klaushoeflich@hotmail.com.
PMID: 25902869 DOI: 10.1186/s13058-015-0564-5
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-19538
    99.49%, PAK 抑制剂
    PAK
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