Advanced

Co-targeting of the PI3K pathway improves the response of BRCA1 deficient breast cancer cells to PARP1 inhibition.

Kimbung, Siker LU ; Biskup, Ewa; Johansson, Ida LU ; Aaltonen, Kristina LU ; Ottosson-Wadlund, Astrid; Gruvberger, Sofia LU ; Cunliffe, Heather; Fadeel, Bengt; Loman, Niklas LU and Berglund, Pontus LU , et al. (2012) In Cancer Letters 319(2). p.232-241
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cancer Letters
volume
319
issue
2
pages
232 - 241
publisher
Elsevier
external identifiers
  • wos:000303487500014
  • pmid:22266096
  • scopus:84859481137
ISSN
1872-7980
DOI
10.1016/j.canlet.2012.01.015
language
English
LU publication?
yes
id
f025e9fd-a1e5-4dfc-870f-1806017a8ab9 (old id 2336116)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22266096?dopt=Abstract
date added to LUP
2012-02-01 22:32:31
date last changed
2017-09-24 04:41:56
@article{f025e9fd-a1e5-4dfc-870f-1806017a8ab9,
  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.},
  author       = {Kimbung, Siker and Biskup, Ewa and Johansson, Ida and Aaltonen, Kristina and Ottosson-Wadlund, Astrid and Gruvberger, Sofia and Cunliffe, Heather and Fadeel, Bengt and Loman, Niklas and Berglund, Pontus and Hedenfalk, Ingrid},
  issn         = {1872-7980},
  language     = {eng},
  number       = {2},
  pages        = {232--241},
  publisher    = {Elsevier},
  series       = {Cancer Letters},
  title        = {Co-targeting of the PI3K pathway improves the response of BRCA1 deficient breast cancer cells to PARP1 inhibition.},
  url          = {http://dx.doi.org/10.1016/j.canlet.2012.01.015},
  volume       = {319},
  year         = {2012},
}