title: Co-targeting of the PI3K pathway improves the response of BRCA1 deficient breast cancer cells to PARP1 inhibition.
abstract: Although pre-clinical and clinical studies on PARP1 inhibitors, alone and in combination with DNA-damaging agents, show promising results, further ways to improve and broaden the scope of application of this therapeutic approach are warranted. To this end, we have investigated the possibility of improving the response of BRCA1 mutant breast cancer cells to PARP1 inhibition by co-targeting the PI3K pathway. Human breast cancer cell lines with or without the expression of BRCA1 and/or PTEN were treated with PARP1 and PI3K inhibitors as single agents and in combination. PARP1 inhibition induced DNA damage conferring a G2/M arrest and decrease in viability, paralleled by the induction of apoptosis. PI3K inhibition alone caused a G1 arrest and decreased cell growth. Most importantly, sequential combination of PARP and PI3K inhibitors interacted synergistically to significantly decrease growth compared to PARP inhibition alone. Global transcriptional profiling revealed that this decrease in growth was associated with down-regulation of macromolecule biosynthesis and the induction of apoptosis. Taken together, these results suggest an improved treatment strategy for BRCA1-mutant and possibly also triple-negative breast cancers with similar molecular defects.
authors.affiliation: Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden; CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Siker
authors.initials: S
authors.lastname: Kimbung
authors.affiliation: Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden; CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Biskup
authors.affiliation: Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden; CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Ida
authors.initials: I
authors.lastname: Johansson
authors.affiliation: Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden; CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Aaltonen
authors.affiliation: Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Astrid
authors.initials: A
authors.lastname: Ottosson-Wadlund
authors.affiliation: Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden; CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Gruvberger-Saal
authors.affiliation: Translational Genomics Research Institute, Phoenix, AZ, United States.
authors.forename: Heather
authors.initials: H
authors.lastname: Cunliffe
authors.affiliation: Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Fadeel
authors.affiliation: Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden; CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Loman
authors.affiliation: Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden; CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Pontus
authors.initials: P
authors.lastname: Berglund
authors.affiliation: Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden; CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden. Electronic address: Ingrid.Hedenfalk@med.lu.se.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hedenfalk
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004359:Drug Therapy, Combination; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019313:BRCA1 Protein; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human