Predictive markers for efficacy of everolimus plus exemestane in patients with luminal HER2-negative metastatic breast cancer

Okazaki, Misato; Horimoto, Yoshiya; Tanabe, Masahiko; Ichikawa, Yuko; Tokuda, Emi; Arakawa, Atsushi; Kobayashi, Toshiyuki; Saito, Mitsue

doi:10.1007/s12032-018-1112-9

Cited by 8 publications

(8 citation statements)

References 27 publications

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“…In a gastric cell line research, expressions of pho-S6K1 Ser424 and pho-AKT Ser473 in rapamycin-resistant cells were higher than that in rapamycin-sensitive cells 46 . Another research also showed that low pho-S6 expression corresponded to response to everolimus-combined therapy and pho-S6K1 overexpression was associated with a poor prognosis 47 .…”

Section: Discussionmentioning

confidence: 96%

Immunofluorescence can assess the efficacy of mTOR pathway therapeutic agent Everolimus in breast cancer models

Kuo

Chen

et al. 2019

Sci Rep

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When breast cancer patients start to exhibit resistance to hormonal therapy or chemotherapy, the mTOR inhibitor everolimus can be considered as an alternative therapeutic agent. Everolimus can deregulate the PI3K/AKT/mTOR pathway and affect a range of cellular functions. In some patients, the agent does not exhibit the desired efficacy and, even worse, not without the associated side effects. This study assessed the use of immunofluorescence (IF) as a modality to fill this unmet need of predicting the efficacy of everolimus prior to administration. Cell viability and MTT assays based on IF intensities of pho-4EBP1 Thr37/46 and pho-S6K1 Ser424 on breast cancer cells (Hs578T, MCF7, BT474, MDA-MB-231) and patient-derived cell culture from metastatic sites (ABC-82T and ABC-16TX1) were interrogated. Results show that independent pho-4EBP1 Thr37/46 and pho-S6K1 Ser424 IF expressions can classify data into different groups: everolimus sensitive and resistant. The combined IF baseline intensity of these proteins is predictive of the efficacy of everolimus, and their intensities change dynamically when cells are resistant to everolimus. Furthermore, mTOR resistance is not only consequence of the AKT/mTOR pathway but also through the LKB1 or MAPK/ERK pathway. The LKB1 and pho-GSK3β may also be potential predictive markers for everolimus.

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Section: Discussionmentioning

confidence: 96%

Immunofluorescence can assess the efficacy of mTOR pathway therapeutic agent Everolimus in breast cancer models

Kuo

Chen

et al. 2019

Sci Rep

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“…We tested two proteins associated with an activated MAPK pathway, p-ERK1/2 and p-S6RP(Ser235/236) in the context of possible benefit from treatment with EVE/EXE, but there was no relation with PFS. The group of Okazaki et al ( 2018 ) have reported in only 18 ER-positive, HER2-negative MBC patients on EVE/EXE, that PFS was not significantly different between patients with high or low p-S6RP(Ser235/236) in primary tumour tissue. For the 55 patients randomised to everolimus plus tamoxifen or tamoxifen alone in the TAMRAD study, p-S6RP(Ser235/236) expression in primary tumour tissue was not associated with TTP (Treilleux et al 2015 ).…”

Section: Discussionmentioning

confidence: 98%

“…IHC analysis of primary tumour tissues from 55 out of 111 patients who participated in the randomised phase II TAMRAD study (Treilleux et al 2015 ) has shown that high levels of p-4EBP1 as well as low levels of p-AKT(Ser473) were associated with improved time-to-progression (TTP) on everolimus plus tamoxifen compared to that on tamoxifen alone. Okazaki et al (Okazaki et al 2018 ) have studied PTEN in primary tumour tissue of only 18 locally advanced BC or MBC patients on standard EVE/EXE, but found no relation with PFS. Although studies, including our attempt, on single PI3K-associated proteins in primary tumour tissue in the context of selecting MBC patients for EVE/EXE are few, it appears that this approach will not be of clinical value.…”

Section: Discussionmentioning

confidence: 99%

PI3K pathway protein analyses in metastatic breast cancer patients receiving standard everolimus and exemestane

Kruger

Opdam

Noort

et al. 2020

J Cancer Res Clin Oncol

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Purpose Everolimus plus exemestane (EVE/EXE) is a registered treatment option for ER-positive, HER2-negative (ER +/HER2-) metastatic breast cancer (MBC), but resistance mechanisms limit efficacy. We aimed to find markers that might help select patients with a higher chance on benefit from EVE/EXE. Methods Immunohistochemistry (IHC) of PTEN, p-AKT(Thr308), p-AKT(Ser473), p-4EBP1, p-p70S6K, p-S6RP(Ser240/244), p-ERK1/2 and p-S6RP (Ser235/236) was performed on primary tumour tissue and on biopsies immediately taken from ER +/HER2- MBC patients before the start of standard EVE/EXE (Eudract 2013-004120-11). Unsupervised hierarchical clustering was executed to create heatmaps to distinguish subgroups of preferentially activated and less-activated PI3K/MAPK proteins. Uni- and multivariate Cox models were used for associations with PFS. Results Primary tumour tissue from 145 patients was retrieved. Median PFS was 5.4 months. Patients without (neo)adjuvant therapy (p = 0.03) or bone only disease (p = 0.04) had longer PFS on EVE/EXE. In primary tumours, neither single proteins nor PI3K/MAPK-associated heatmap subgroups were significantly associated with PFS. In 21 patients a non-osseous biopsy obtained before dosing was useful for continuous scoring, which demonstrated upregulation of several proteins as compared to readings in corresponding primary tumour tissues. These comparisons revealed that increased expression of p-4EBP1 was significantly associated with worse PFS (multivariate HR 3.69, p = 0.05). Conclusions IHC of single proteins or heatmap subgroups of the differentially activated PI3K/MAPK pathways was not able to discriminate patients on EVE/EXE with poor or better PFS. Upregulation of p-4EBP1 in pre-treatment biopsies as compared to levels in primary tumours pointed towards shorter PFS.

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“…The proof of the cooperation of the ER and PI3K pathways in the advancement of tumors arose from a clinical study (19,20). A remarkable improvement was observed in the progressive defense of ER-positive breast tumor patients who underwent with everolimus treatment, an mTOR inhibitor, combined with exemestane, an inhibitor for the anti-estrogen aromatase (21,22).…”

Section: Introductionmentioning

confidence: 99%

Alpelisib Inhibits PIK3CA-Mutant Breast Cancer Growth Through AKT-Dependent Bim Induction and Mcl-1 Degradation

Tan¹,

Zhang²,

Liu³

et al. 2020

Preprint

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Abstract Background: PIK3CA mutations are common genomic alterations in estrogen receptor (ER)-positive breast cancers, currently, the development of selective PI3Kα (phosphatidylinositol 3-kinase α) inhibitors is ongoing. The mechanisms contributing to the anticancer activity of alpelisib in PIK3CA-mutant breast cancer cells and the mechanism of acquired resistance to alpelisib remain elusive. Methods: Drug-sensitive cell lines were exposed to alpelisib to establish alpelisib-resistant cell lines. Western blotting was used to assess changes in protein expression. Apoptosis was evaluated by ﬂow cytometry. In vivo with mouse xenograft models and in vitro colony formation and MTS and assay were carried out to determine the growth inhibitory effects of the tested drugs. Protein half-lives were examined and proteasome inhibitors were used to estimate protein degradation. Gene knockdown was carried out using shRNA or siRNA. Results: In the present study, we report the potent induction of apoptosis by alpelisib in PIK3CA-mutant breast cancer cell lines. AKT phosphorylation suppression, AKT/Foxo3a-dependent Bim induction, and AKT/GSK-3β-dependent Mcl-1 degradation were observed. Apoptosis induced by alpelisib was attenuated by Mcl-1 (4A) overexpression or Bim suppression. Furthermore, alpelisib could not modulate Mcl-1 or Bim levels in cell lines that were resistant to alpelisib. AKT inhibitor and alpelisib combination restored the sensitivity of alpelisib-resistant cells to growth inhibition and apoptosis in vitro and in vivo. Conclusions: Therefore, modulation of Mcl-1 degradation and AKT-dependent Bim induction are crucial for mediating the resistance and sensitivity of PIK3CA-mutant breast tumor cells to alpelisib, thus making it a productive strategy for overcoming acquired resistance to alpelisib.

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Predictive markers for efficacy of everolimus plus exemestane in patients with luminal HER2-negative metastatic breast cancer

Cited by 8 publications

References 27 publications

Immunofluorescence can assess the efficacy of mTOR pathway therapeutic agent Everolimus in breast cancer models

Immunofluorescence can assess the efficacy of mTOR pathway therapeutic agent Everolimus in breast cancer models

PI3K pathway protein analyses in metastatic breast cancer patients receiving standard everolimus and exemestane

Alpelisib Inhibits PIK3CA-Mutant Breast Cancer Growth Through AKT-Dependent Bim Induction and Mcl-1 Degradation

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