Oncotarget

Research Papers:

Reduced PAK1 activity sensitizes FA/BRCA-proficient breast cancer cells to PARP inhibition

Olga Villamar, Tatiana Y. Prudnikova, Daniela Araiza-Olivera, Carlos Perez-Plasencia, Neil Johnson, Andrea J. Bernhardy, Michael Slifker, Catherine Renner, Jonathan Chernoff and Luis E. Arias-Romero _

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Oncotarget. 2016; 7:76590-76603. https://doi.org/10.18632/oncotarget.12576

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Abstract

Olga Villamar Cruz1,*, Tatiana Y. Prudnikova2,*, Daniela Araiza-Olivera2, Carlos Perez-Plasencia1, Neil Johnson3, Andrea J. Bernhardy3, Michael Slifker4, Catherine Renner5, Jonathan Chernoff2 and Luis E. Arias-Romero1

1 UBIMED, Facultad de Estudios Superiores-Iztacala, UNAM, Tlalnepantla, Estado de México, Mexico

2 Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA

3 Experimental Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA

4 Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA, USA

5 Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA

* These authors have contributed equally to this work

Correspondence to:

Luis E. Arias-Romero, email:

Jonathan Chernoff, email:

Keywords: transformation, PAK1, DNA repair, Fanconi Anemia, small molecule inhibitor

Received: June 21, 2016 Accepted: October 07, 2016 Published: October 11, 2016

Abstract

Cells that are deficient in homologous recombination, such as those that have mutations in any of the Fanconi Anemia (FA)/BRCA genes, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, FA/BRCA-deficient tumors represent a small fraction of breast cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. The gene encoding the serine-threonine protein kinase p21-activated kinase 1 (PAK1) is amplified and/or overexpressed in several human cancer types including 25-30% of breast tumors. This enzyme controls many cellular processes by phosphorylating both cytoplasmic and nuclear substrates. Here, we show that depletion or pharmacological inhibition of PAK1 down-regulated the expression of genes involved in the FA/BRCA pathway and compromised the ability of cells to repair DNA by Homologous Recombination (HR), promoting apoptosis and reducing colony formation. Combined inhibition of PAK1 and PARP in PAK1 overexpressing breast cancer cells had a synergistic effect, enhancing apoptosis, suppressing colony formation, and delaying tumor growth in a xenograft setting. Because reduced PAK1 activity impaired FA/BRCA function, inhibition of this kinase in PAK1 amplified and/or overexpressing breast cancer cells represents a plausible strategy for expanding the utility of PARP inhibitors to FA/BRCA-proficient cancers.


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