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Villamar Cruz O , Prudnikova TY , Araiza-Olivera D , Perez-Plasencia C , Johnson N , Bernhardy AJ , Slifker M , Renner C , Chernoff J , Arias-Romero LE
Reduced PAK1 activity sensitizes FA/BRCA-proficient breast cancer cells to PARP inhibition
Oncotarget. 2016 Oct 11;7(47) :76590-76603
PMID: 27740936    PMCID: PMC5363532    URL: https://www.ncbi.nlm.nih.gov/pubmed/27740936
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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.
1949-2553 Villamar Cruz, Olga Prudnikova, Tatiana Y Araiza-Olivera, Daniela Perez-Plasencia, Carlos Johnson, Neil Bernhardy, Andrea J Slifker, Michael Renner, Catherine Chernoff, Jonathan Arias-Romero, Luis E Journal article United States Oncotarget. 2016 Oct 11. doi: 10.18632/oncotarget.12576.