Dual mTOR Kinase Inhibitor MLN0128 Sensitizes HR+/HER2+ Breast Cancer Patient-Derived Xenografts to Trastuzumab or Fulvestrant

Hsu, Pei Yin; Wu, Victoria Shang; Kanaya, Noriko; Petrossian, Karineh; Hsu, Hang Kai; Nguyen, Duc T.; Schmolze, Daniel; Kai, Masaya; Liu, Chun Yu; Lu, Hannah; Vito, Courtney; Kruper, Laura; Mortimer, Joanne; Chen, Shiuan

doi:10.1158/1078-0432.ccr-17-1983

Cited by 19 publications

(46 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, single cell preparations exhibited variation of ER and RB expression which is expected due to the heterogeneity in the tumor (Figure 5B ). This observation also agreed with the IHC staining of this PDX which is approximately 40-50% ER+ [ 37 ]. Moreover, as ER coverage reads increased, there is no correlation with the RB expression; thus, ER and RB are two independent factors in the cell cycle (Figure 5B ).…”

Section: Resultssupporting

confidence: 87%

“…COH-SC31, generated in our laboratory, is a unique PDX tumor model. While it is triple positive (ER/PR/HER2), it is also Herceptin resistant; thus, it completely depends on estrogen for growth [ 37 ]. Thus, this is a relevant model to demonstrate the molecular action of palbociclib because it depends on activated ER for growth, although it is HER2-positive.…”

Section: Resultsmentioning

confidence: 99%

“…To authentically reflect the innate heterogeneity of a tumor, PDX breast cancer model COH-SC31 was considered a valuable tool to test how the levels of ER, involved in cell cycle progression, affect the tumor response to CDK4/6 inhibitors at the single cell level. In order to isolate intact epithelial cells, we took advantage that this tumor is triple positive (ER/PR/HER2), growth dependent on estrogen and it is Herceptin resistant with homogenous HER2 expression [ 37 ].…”

Section: Resultsmentioning

confidence: 99%

“…Individual cells in clinically defined ER+ tumors have different levels of ER expression. COH-SC31 tumor exhibits 40-50% ER+ cells; thus, 50-60% of the cells are defined as ER negative using IHC analysis [ 37 ]. IHC detected ER expression levels are not a predictive marker for CDK4/6 inhibitor response, as suggested by the different response to estrogen in ER+ PDX tumor models [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

ERα-mediated cell cycle progression is an important requisite for CDK4/6 inhibitor response in HR+ breast cancer

Petrossian

Kanaya

et al. 2018

Oncotarget

Self Cite

View full text Add to dashboard Cite

While ER has multiple biological effects, ER-cyclin D1-CDK4/6-RB is a critical pathway for the action of estrogen on the cell cycle, especially for breast cancers that rely on estrogen for growth. The latest and most efficient CDK4/6 inhibitors target the phosphorylation of retinoblastoma (RB) tumor suppressor gene; thus, altering levels of many cell cycle molecules. Estrogen receptor (ER)+/HER2- breast cancers have shown great progression free survival when CDK4/6 inhibitors are combined with endocrine therapies. Here we report the mechanism of antiestrogen (fulvestrant) combination with CDK4/6 inhibitors is due to synergism in the suppression of ER-mediated cell cycle progression. Furthermore, we performed single cell analysis of cells from an estrogen dependent/hormone receptor-positive patient derived xenograft (PDX) tumor model treated with palbociclib. These single cells expressed various levels of ER and RB which are involved in cell cycle regulation; and the response to palbociclib treatment relies not only on the ER-cyclin D1-CDK4/6-RB pathway but it is also dependent on elevated levels of ER and/or RB. Our preclinical studies show that palbociclib response is dependent on cells with ER, which is directly involved in cell cycle progression in hormone receptor positive (HR+) breast cancer.

show abstract

Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

ERα-mediated cell cycle progression is an important requisite for CDK4/6 inhibitor response in HR+ breast cancer

Petrossian

Kanaya

et al. 2018

Oncotarget

Self Cite

View full text Add to dashboard Cite

show abstract

“…The reported results revealed that apart from standard trastuzumab therapies, the combination with the dual mammalian target of rapamycin (mTOR) complex inhibitor impeded tumor growth. Thus, this study opens the door for personalized medicine clinical trials (101).…”

Section: Main Type Of Protein Array Methods Analytical/antibody/indirementioning

confidence: 85%

Protein microarray technology: Assisting personalized medicine in oncology (Review)

2019

View full text Add to dashboard Cite

Among proteomics technologies, protein microarray, over the past last years, has gained an increased momentum in the biomarkers discovery domain. The characteristics of protein microarray, namely that it is a high-throughput tool, it provides a high specificity and only requires a minute amount of biological samples, render it a suitable tool for searching, quantifying and validating biomarkers in various pathologies. Protein microarray is based on the specific antigen-antibody reaction, such as any enzyme-linked immunosorbent assay, the specific reaction occurring on a miniaturized support (chip or slide), thus having the advantage of simultaneous evaluation of tens to thousands of molecules in small samples with a highly specific recognition for the detection system. In this review, we highlight the history of protein microarray technologies development and discuss this technology is stepping into the future. We present personalized medicine goals and discuss how protein microarray can aid in these goals, with an emphasis on several oncological diseases. We also discuss how protein technology has been used in diseases, such as lung, breast cancers, as well as in other diseases that, over the past last years, have taken advantage of this proteomic endeavor.

show abstract

Molecular features of luminal breast cancer defined through spatial and single‐cell transcriptomics

Yoshitake,

Mori,

et al. 2024

Clinical & Translational Med

Self Cite

View full text Add to dashboard Cite

BackgroundIntratumour heterogeneity is a hallmark of most solid tumours, including breast cancers. We applied spatial transcriptomics and single‐cell RNA‐sequencing on patient‐derived xenografts (PDXs) to profile spatially resolved cell populations within oestrogen receptor‐positive (ER+) breast cancer and to elucidate their importance in oestrogen‐dependent tumour growth.MethodsTwo PDXs of ‘ER‐high’ breast cancers with opposite oestrogen‐mediated growth responses were investigated: oestrogen‐suppressed GS3 (80–100% ER) and oestrogen‐dependent SC31 (40–90% ER) models. The observation was validated via single‐cell analyses on an ‘ER‐low’ PDX, GS1 (5% ER). The results from our spatial and single‐cell analyses were further supported by a public ER+ breast cancer single‐cell dataset and protein‐based dual immunohistochemistry (IHC) of SC31 examining important luminal cancer markers (i.e., ER, progesterone receptor and Ki67). The translational implication of our findings was assessed by clinical outcome analyses on publicly available cohorts.ResultsOur space‐gene‐function study revealed four spatially distinct compartments within ER+ breast cancers. These compartments showed functional diversity (oestrogen‐responsive, proliferative, hypoxia‐induced and inflammation‐related). The ‘proliferative’ population, rather than the ‘oestrogen‐responsive’ compartment, was crucial for oestrogen‐dependent tumour growth, leading to the acquisition of luminal B‐like features. The cells expressing typical oestrogen‐responsive genes like PGR were not directly linked to oestrogen‐dependent proliferation. Dual IHC analyses demonstrated the distinct contribution of the Ki67+ proliferative cells toward oestrogen‐mediated growth and their response to a CDK4/6 inhibitor. The gene signatures derived from the proliferative, hypoxia‐induced and inflammation‐related compartments were significantly correlated with worse clinical outcomes, while patients with the oestrogen‐responsive signature showed better prognoses, suggesting that this compartment would not be directly associated with oestrogen‐dependent tumour progression.ConclusionsOur study identified the gene signature in our ‘proliferative’ compartment as an important determinant of luminal cancer subtypes. This ‘proliferative’ cell population is a causative feature of luminal B breast cancer, contributing toward its aggressive behaviours.

show abstract

Dual mTOR Kinase Inhibitor MLN0128 Sensitizes HR+/HER2+ Breast Cancer Patient-Derived Xenografts to Trastuzumab or Fulvestrant

Abstract: Purpose: Therapeutic strategies against hormonal receptorpositive (HR þ

Cited by 19 publications

References 48 publications

ERα-mediated cell cycle progression is an important requisite for CDK4/6 inhibitor response in HR+ breast cancer

ERα-mediated cell cycle progression is an important requisite for CDK4/6 inhibitor response in HR+ breast cancer

Protein microarray technology: Assisting personalized medicine in oncology (Review)

Molecular features of luminal breast cancer defined through spatial and single‐cell transcriptomics

Contact Info

Product

Resources

About