title: Reduced PAK1 activity sensitizes FA/BRCA-proficient breast cancer cells to PARP inhibition.
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.
authors.affiliation: UBIMED, Facultad de Estudios Superiores-Iztacala, UNAM, Tlalnepantla, Estado de México, Mexico.
authors.forename: Olga
authors.initials: O
authors.lastname: Villamar Cruz
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Tatiana Y
authors.initials: TY
authors.lastname: Prudnikova
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Araiza-Olivera
authors.affiliation: UBIMED, Facultad de Estudios Superiores-Iztacala, UNAM, Tlalnepantla, Estado de México, Mexico.
authors.forename: Carlos
authors.initials: C
authors.lastname: Perez-Plasencia
authors.affiliation: Experimental Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Johnson
authors.affiliation: Experimental Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Bernhardy
authors.affiliation: Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Slifker
authors.affiliation: Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Renner
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chernoff
authors.affiliation: UBIMED, Facultad de Estudios Superiores-Iztacala, UNAM, Tlalnepantla, Estado de México, Mexico.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Arias-Romero
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D051856:Fanconi Anemia Complementation Group Proteins / Q000172:deficiency / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D059765:Homologous Recombination; D006801:Humans; D051379:Mice; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051856:Fanconi Anemia Complementation Group Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D054462:p21-Activated Kinases
keywords: DNA repair; PAK1; small molecule inhibitor; transformation; Fanconi anemia