Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer

Simple item page
dc.contributor.authorSanchez, Cesar G.
dc.contributor.authorMa, Cynthia X.
dc.contributor.authorCrowder, Robert J.
dc.contributor.authorGuintoli, Therese.
dc.contributor.authorPhommaly, Chanpheng.
dc.contributor.authorGao, Feng.
dc.contributor.authorLin, Li.
dc.contributor.authorEllis, Matthew J.
dc.date.accessioned2019-10-17T18:22:27Z
dc.date.available2019-10-17T18:22:27Z
dc.date.issued2011
dc.date.updated2019-10-14T19:03:41Z
dc.description.abstractAbstract Introduction Inhibition of phosphatidylinositol-3-kinase (PI3K) induces apoptosis when combined with estrogen deprivation in estrogen receptor (ER)-positive breast cancer. The aims of the present study were to identify effective PI3K pathway inhibitor and endocrine therapy combinations, to evaluate the effect of PI3K pathway mutations and estrogen dependency on tumor response, and to determine the relevance of PIK3CA mutation in recurrent disease. Methods The PI3K catalytic subunit inhibitor BKM120, the mammalian target of rapamycin (mTOR) inhibitor RAD001 and the dual PI3K/mTOR inhibitor BGT226 were tested against ER-positive breast cancer cell lines before and after long-term estrogen deprivation (LTED). The impact of estradiol deprivation and the ER downregulator fulvestrant on PI3K pathway inhibitor-induced apoptosis was assessed. PIK3CA hotspot mutation analysis was performed in 51 recurrent or metastatic breast cancers and correlated with ER status and survival. Results Drug-induced apoptosis was most marked in short-term estrogen-deprived cells with PIK3CA mutation and phosphatase and tensin homolog loss. Apoptosis was most highly induced by BGT226, followed by BKM120, and then RAD001. Estradiol antagonized PI3K inhibitor-induced apoptosis following short-term estrogen deprivation, emphasizing a role for estrogen-deprivation therapy in promoting PI3K inhibitor activity in the first-line setting. ER-positive MCF7 LTED cells exhibited relative resistance to PI3K pathway inhibition that was reversed by fulvestrant. In contrast, T47D LTED cells exhibited ER loss and ER-independent PI3K agent sensitivity. PIK3CA mutation was prevalent in relapsed ER-positive disease (48%) and was associated with persistent ER positivity and a late relapse pattern. Conclusions Estrogen deprivation increased the apoptotic effects of PI3K and dual PI3K/mTOR inhibitors in ER-positive disease, providing a rationale for PI3K/aromatase inhibitor combinations as first-line therapy. In LTED cells, differential effects on ER expression may be a relevant consideration. When ER was persistently expressed, fulvestrant strongly promoted PI3K drug activity. When ER was lost, PI3K inhibitor monotherapy was sufficient to induce high-level apoptosis. Although tumors with PIK3CA mutation had a late recurrence pattern, these mutations were common in metastatic disease and were most often associated with persistent ER expression. Targeting PIK3CA mutant tumors with a PI3K pathway inhibitor and fulvestrant is therefore a feasible strategy for aromatase-inhibitor-resistant ER-positive relapsed breast cancer.
dc.fuente.origenBiomed Central
dc.identifier.citationBreast Cancer Research. 2011 Mar 01;13(2):R21
dc.identifier.doi10.1186/bcr2833
dc.identifier.urihttps://doi.org/10.1186/bcr2833
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/26839
dc.issue.numeroNo. R21
dc.language.isoen
dc.pagina.final17
dc.pagina.inicio1
dc.revistaBreast Cancer Researches_ES
dc.rights.holderSanchez et al.; licensee BioMed Central Ltd.
dc.subject.ddc610
dc.subject.deweyMedicina y saludes_ES
dc.subject.otherCáncer de mama -Terapiaes_ES
dc.subject.otherFosfatidilinositol 3-Quinasaes_ES
dc.subject.otherEstrógenoses_ES
dc.titlePreclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast canceres_ES
dc.typeartículo
dc.volumenVol. 13
sipa.codpersvinculados135644
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
13058_2010_Article_2652.pdf
Size:
2.35 MB
Format:
Adobe Portable Document Format
Description:
Download
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
0 B
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Artículos de revistas