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Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen
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Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells

Christy C Ong1, Adrian M Jubb, Peter M Haverty

  • 1Department of Translational Oncology, Genentech, Inc, South San Francisco, CA 94080, USA.

Proceedings of the National Academy of Sciences of the United States of America
|April 13, 2011
PubMed

Insights

p21-activated kinases (PAKs) are crucial in cancer. PAK1 dysregulation in breast and lung cancers suggests it drives tumor growth and survival, offering new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • p21-activated kinases (PAKs) are serine/threonine protein kinases mediating Rac and Cdc42 GTPase functions.
  • PAK1 is involved in Ras-driven tumorigenesis, growth factor receptor signaling, and morphogenetic processes controlling cell polarity, invasion, and actin cytoskeleton organization.

Purpose of the Study:

  • To investigate the role of PAK1 in tumorigenesis by analyzing its genomic copy number and expression in breast, lung, and head and neck tumors.
  • To evaluate the therapeutic potential of PAK1 inhibition in relevant cancer models.

Main Methods:

  • Genomic copy number and protein expression analysis of PAK1 in a large panel of breast, lung, and head and neck tumors.
  • In vitro and in vivo studies involving selective PAK1 inhibition in cancer cells.
  • Profiling of non-small cell lung cancer (NSCLC) cells with pathway-targeted small-molecule inhibitors.

Main Results:

  • PAK1 genomic amplification at 11q13 was prevalent in luminal breast cancer, associated with lymph node metastasis. PAK1 inhibition induced apoptosis in amplified breast cancer cells.
  • Strong PAK1 expression was observed in squamous NSCLCs; PAK1 inhibition delayed cell-cycle progression.
  • Combination therapies, including with apoptosis inhibitors, showed synergistic effects, enhancing apoptosis in NSCLC cells.

Conclusions:

  • PAK1 is dysregulated in breast and squamous NSCLCs, playing a significant role in cellular survival and proliferation.
  • Targeting PAK1, potentially in combination with apoptosis inhibitors, represents a promising therapeutic strategy for these cancers.

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