Abstract 1876: Reduced Pak1 activity sensitizes FA/BRCA-proficient breast cancer cells to PARP inhibition

Abstract

Abstract Cells that are deficient in homologous recombination, such as those that have mutations in any of the Fanconi Anemia (FA)/BRCA pathway genes, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, FA/BRCA-deficient tumors represent only a small fraction of breast cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. p21-activated kinase 1 (Pak1) is a serine/threonine protein kinase located in the chromosome 11q13 and is amplified and/or overexpressed in several human cancer types including 25-30% of breast tumors. This enzyme controls many cellular processes by phosphorylating its downstream substrates; in addition to its role in the cytoplasm, Pak1 also affects gene transcription due to its nuclear localization and association with chromatin. It is now recognized that Pak1 activation is a component of the DNA damage response. Here, we show that depletion or inhibition of Pak1 down-regulated the expression of several genes involved in the FA/BRCA pathway and compromised the ability of cells to repair DNA by homologous recombination, induced cell cycle arrest, promoted apoptosis and resulted in reduced colony formation. Combined inhibition of Pak1 and PARP in pak1 amplified breast cancer cells had a synergistic effect, enhanced apoptosis, resulted in reduced colony formation and delayed tumor growth in a xenograft setting. Inhibition of Pak1 did not sensitize non-transformed or Pak1 non-amplified cells to inhibition of PARP. Because reduced Pak1 activity impaired FA/BRCA function and consequently, repair by homologous recombination, 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. Citation Format: Olga Villamar-Cruz, Tatiana Prudnikova, Neil Johnson, Jonathan Chernoff, Luis E. Arias Romero. Reduced Pak1 activity sensitizes FA/BRCA-proficient breast cancer cells to PARP inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1876.