Co-targeting of the PI3K pathway improves the response of BRCA1 deficient breast cancer cells to PARP1 inhibition.
Författare
Summary, in English
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.
Avdelning/ar
- Bröstcancer-genetik
- Experimentell patologi, Malmö
- Bröst- och ovarialcancer
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publiceringsår
2012
Språk
Engelska
Sidor
232-241
Publikation/Tidskrift/Serie
Cancer Letters
Volym
319
Issue
2
Länkar
Dokumenttyp
Artikel i tidskrift
Förlag
Elsevier
Ämne
- Cancer and Oncology
Status
Published
Forskningsgrupp
- Experimental Pathology, Malmö
- Breast and Ovarian Cancer Genomics
ISBN/ISSN/Övrigt
- ISSN: 1872-7980