Effects of the combination of RAD001 and docetaxel on breast cancer stem cells

Zhang, Xiaobei; Zhang, Sheng; Liu, Yan; Liu, Jingjing; Ma, Yi; Zhu, Yuanxi; Zhang, Jin

doi:10.1016/j.ejca.2012.02.053

Cited by 45 publications

(35 citation statements)

References 24 publications

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“…Further, mTOR inhibitors like rapamycin and everolimus have been shown to inhibit growth of triple-negative breast cancer cell lines, reverse doxorubicin resistance and enhance docetaxel effects in vitro. [163][164][165] Finally, experimental evidence has linked elevated Akt activity to enhanced p53 degradation, 166 and there is evidence for synergistic interactions between PI3K and poly(ADP-ribose) polymerase (PARP) inhibition, 167 thus linking Akt activity to the p53 pathway as well as homologous end repair.…”

Section: Activating Mutations In the Pten/pi3k/mtor Pathway As A Causmentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.

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Section: Activating Mutations In the Pten/pi3k/mtor Pathway As A Causmentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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“…3 In preclinical studies, everolimus exerts synergistic anticancer effects with docetaxel in a variety of cell lines. 4,5 We previously reported that docetaxel and everolimus could be combined safely in patients with advanced NSCLC at the doses of 60 mg/m 2 and 5 mg orally once daily, respectively. 6 The dose-limiting toxicities were grade 3 fatigue, grade 3 mucositis, and grade 3/4 neutropenia with fever.…”

mentioning

confidence: 99%

Phase II Study of Docetaxel in Combination with Everolimus for Second- or Third-Line Therapy of Advanced Non–Small-Cell Lung Cancer

Ramalingam

Owonikoko

Behera

et al. 2013

Journal of Thoracic Oncology

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We conducted a phase II study of docetaxel in combination with everolimus, a mammalian target of rapamycin (mTOR) inhibitor, for salvage therapy of advanced non–small-cell lung cancer (NSCLC) based on promising preclinical and early-phase clinical data. Patients with advanced-stage NSCLC treated with one or two previous systemic therapy regimens were given docetaxel (60 mg/m2) and everolimus (5 mg orally once daily on days 1–19) every 3 weeks. Archived tumor specimens were evaluated for markers of mTOR pathway activation (total and phosphorylated mTOR, Akt, S6, eIF4e, and 4EBP1). Twenty-eight patients were enrolled (median age: 62 years; male: 13; Caucasians: 19; adenocarcinoma: 20; performance status 0, 3; performance status 1, 23; 1 previous regimen, 16). A median of 3.5 cycles of therapy was administered. Two patients experienced partial response and 15 had stable disease (clinical benefit rate, 70%). The 6-month progression-free survival rate was 5%, and the median overall survival was 9.6 months. Low pAkt expression correlated with clinical benefit rate (p = 0.01) but not with progression-free survival or overall survival. The combination of everolimus and docetaxel was tolerated well, but the efficacy was relatively modest in an unselected population of patients with NSCLC.

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“…RAD001 was shown to have an additive effect to docetaxel in reducing the volumes of the xenograft tumours induced in mice by MDA-MB-231 stem cells 25 . Similarly, we have recently shown that combined RAD001 and docetaxel treatment had synergy in reducing PC3 tumour growth in nude mice 16 .…”

Section: Discussionmentioning

confidence: 98%

Combination of RAD001 (everolimus) and docetaxel reduces prostate and breast cancer cell VEGF production and tumour vascularisation independently of sphingosine-kinase-1

Alshaker¹,

Wang²,

Böhler³

et al. 2017

Sci Rep

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Resistance to docetaxel is a key problem in current prostate and breast cancer management. We have recently discovered a new molecular mechanism of prostate cancer docetaxel chemoresistance mediated by the mammalian target of rapamycin (mTOR)/sphingosine-kinase-1 (SK1) pathway. Here we investigated the influence of this pathway on vascular endothelial growth factor (VEGF) production and tumour vascularisation in hormone resistant prostate and breast cancer models. Immunofluorescent staining of tumour sections from human oestrogen receptor (ER)-negative breast cancer patients showed a strong correlation between phosphorylated P70S6 kinase (mTOR downstream target), VEGF and SK1 protein expression. In hormone-insensitive prostate (PC3) and breast (MDA-MB-231 and BT-549) cancer cell lines the mTOR inhibitor RAD001 (everolimus) has significantly inhibited SK1 and VEGF expression, while low dose (5 nM) docetaxel had no significant effect. In these cell lines, SK1 overexpression slightly increased the basal levels of VEGF, but did not block the inhibitory effect of RAD001 on VEGF. In a human prostate xenograft model established in nude mice, RAD001 alone or in combination with docetaxel has suppressed tumour growth, VEGF expression and decreased tumour vasculature. Overall, our data demonstrate a new mechanism of an independent regulation of SK1 and VEGF by mTOR in hormone-insensitive prostate and breast cancers.

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Effects of the combination of RAD001 and docetaxel on breast cancer stem cells

Cited by 45 publications

References 24 publications

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Phase II Study of Docetaxel in Combination with Everolimus for Second- or Third-Line Therapy of Advanced Non–Small-Cell Lung Cancer

Combination of RAD001 (everolimus) and docetaxel reduces prostate and breast cancer cell VEGF production and tumour vascularisation independently of sphingosine-kinase-1

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