Use of dual mTOR inhibitor MLN0128 against everolimus-resistant breast cancer

Petrossian, Karineh; Nguyen, Duc T.; Lo, Chiao; Kanaya, Noriko; Cui, Yvonne Xiaoyong; Huang, Chiun‐Sheng; Chen, Shiuan

doi:10.1007/s10549-018-4779-x

Cited by 13 publications

(10 citation statements)

References 36 publications

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“…So far, another dual mTOR inhibitor, MLN0128 is used only in vitro on cell models against everolimus-resistant breast cancer, and it inhibits the AKT phosphorylation. MLN0128 may suppress the proliferation of this kind of cell [ 195 ]. Bostner J and co-workers detected that raptor protein expression in the nucleus was increased in ER/PgR-positive and HER2-negative tumors with low grade, further associated with the luminal A subtype.…”

Section: Mtor Inhibitors: Everolimus and Temsirolimusmentioning

confidence: 99%

PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects

Miricescu

Totan

Stănescu-Spînu

et al. 2020

IJMS

478

263

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Breast cancer is a serious health problem worldwide, representing the second cause of death through malignancies among women in developed countries. Population, endogenous and exogenous hormones, and physiological, genetic and breast-related factors are involved in breast cancer pathogenesis. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) is a signaling pathway involved in cell proliferation, survival, invasion, migration, apoptosis, glucose metabolism and DNA repair. In breast tumors, PIK3CA somatic mutations have been reported, located in exon 9 and exon 20. Up to 40% of PIK3CA mutations are estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) -negative in primary and metastatic breast cancer. HER2 is overexpressed in 20–30% of breast cancers. HER1, HER2, HER3 and HER4 are membrane receptor tyrosine kinases involved in HER signaling to which various ligands can be attached, leading to PI3K/AKT activation. Currently, clinical studies evaluate inhibitors of the PI3K/AKT/mTOR axis. The main purpose of this review is to present general aspects of breast cancer, the components of the AKT signaling pathway, the factors that activate this protein kinase B, PI3K/AKT-breast cancer mutations, PI3K/AKT/mTOR-inhibitors, and the relationship between everolimus, temsirolimus and endocrine therapy.

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Section: Mtor Inhibitors: Everolimus and Temsirolimusmentioning

confidence: 99%

PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects

Miricescu

Totan

Stănescu-Spînu

et al. 2020

IJMS

478

263

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“…AZD-2014, a dual mTORC1/2 inhibitor, showed superior activity than everolimus in vitro and in vivo in renal cell carcinoma [79] but demonstrate inferior efficacy in patients with renal cell carcinoma [80]. Therefore, although preliminary studies showed promising efficacy of dual mTOR inhibitors in various of cancers [81,82], the clinical significance should still be investigated in clinical trials to prove their activities in cancer treatment [83].…”

Section: Mtor Inhibitorsmentioning

confidence: 99%

mTOR Inhibitors in Advanced Biliary Tract Cancers

Chen

Yeh

2019

IJMS

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Patients with advanced biliary tract cancers (BTCs), including cholangiocarcinoma (CCA), have poor prognosis so novel treatment is warranted for advanced BTC. In current review, we discuss the limitations of current treatment in BTC, the importance of mTOR signalling in BTC, and the possible role of mTOR inhibitors as a future treatment in BTC. Chemotherapy with gemcitabine-based chemotherapy is still the standard of care and no targeted therapy has been established in advanced BTC. PI3K/AKT/mTOR signaling pathway linking to several other pathways and networks regulates cancer proliferation and progression. Emerging evidences reveal mTOR activation is associated with tumorigenesis and drug-resistance in BTC. Rapalogs, such as sirolimus and everolimus, partially inhibit mTOR complex 1 (mTORC1) and exhibit anti-cancer activity in vitro and in vivo in BTC. Rapalogs in clinical trials demonstrate some activity in patients with advanced BTC. New-generation mTOR inhibitors against ATP-binding pocket inhibit both TORC1 and TORC2 and demonstrate more potent anti-tumor effects in vitro and in vivo, however, prospective clinical trials are warranted to prove its efficacy in patients with advanced BTC.

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“…Acquiring the resistance to mTOR inhibitors (most commonly rapamycin and its derivates) was detected in various tumours' models in vitro as well as in vivo in patients suffering from such conditions as i.a. breast cancers, gliomas 3 , 4 , 31 . The toxicity of mTOR inhibitors is widely known, the most commonly hematologic, gastrointestinal and metabolic side effects are observed.…”

Section: Discussionmentioning

confidence: 99%

“…TORC1 regulates mostly protein synthesis by phosphorylation of translation factors, TORC2 controls cell survival and cytoskeleton functions, both complexes are linked by AKT 3 .…”

Section: Introductionmentioning

confidence: 99%

Gemcitabine and Selected mTOR Inhibitors in Uterine Sarcomas and Carcinosarcoma Cells- an Isobolographic Analysis

Bobinski¹,

Okła²,

Łuszczki³

et al. 2020

Int. J. Med. Sci.

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Introduction: mTOR inhibitors are anticancer agents affecting mTOR/AKT/PI3K pathway that is one of the most important in human cancer cells. Hyperactivation of mTOR/AKT/PI3K and overexpression of this pathway members are frequently reported in uterine sarcoma and carcinosarcoma. Present study is aimed to assess the activity of the two mTOR inhibitors (rapamycin - RAP and sapanisertib - MLN) as a single agent and combined with gemcitabine (GEM, one of substances commonly used in systemic anticancer treatment) in uterine sarcoma and carcinosarcoma in vitro models. Material and methods: SK-UT-1 and SK-UT1-B (uterine carcinosarcoma), MES-SA (leiomyosarcoma) and ESS-1 (endometrial stromal sarcoma) cell lines were used. An MTT assay was performed to examine the cytotoxicity of RAP, MLN and mixtures: RAP+MLN, RAP+GEM, MLN+GEM against these cells. The interactions between tested compounds were assessed in isobolographic analysis. Results and conclusions: Carcinosarcoma cell lines (both SK-UT-1 and SK-UT-1B) do not respond to RAP and respond relatively weakly to MLN treatment. Additive and supraadditive effects were noted for combined treatment with GEM and MLN. Endometrial stromal sarcoma cell line (ESS-1) occured to be sensitive to both RAP and MLN, but the response was stronger for MLN. Additive effect of all tested drug combinations was observed for ESS-1. Leiomyosarcoma cell line (MES-SA) was found sensitive to both mTOR inhibitors. Additive effects in combinations of GEM, RAP and MLN were observed, what makes them promising for future preclinical and clinical trials. Additivity with slight tendency towards antagonism between GEM and MLN observed in MES-SA cell line is unexpected finding and might prompt the mechanistic research aimed to explain this phenomenon.

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Use of dual mTOR inhibitor MLN0128 against everolimus-resistant breast cancer

Abstract: Among the many signaling transduction pathways, which are altered post everolimus resistance, targeting dual mTORC1/2 is a possible option for patients who have recurrent disease from previous everolimus treatment.

Cited by 13 publications

References 36 publications

PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects

PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects

mTOR Inhibitors in Advanced Biliary Tract Cancers

Gemcitabine and Selected mTOR Inhibitors in Uterine Sarcomas and Carcinosarcoma Cells- an Isobolographic Analysis

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