A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer

Savage, Paul; Blanchet-Cohen, Alexis; Revil, Timothée; Badescu, Dunarel; Saleh, Sadiq M.I.; Wang, Yuchang; Zuo, Dongmei; Liu, Leah; Bertos, Nicholas; Muñoz-Ramos, Valentina; Basik, Mark; Petrecca, Kevin; Asselah, Jamil; Meterissian, Sarkis; Guiot, Marie‐Christine; Ömeroğlu, Atilla; Kleinman, Claudia L.; Park, Morag; Ragoussis, Jiannis

doi:10.1016/j.celrep.2017.10.015

Cited by 71 publications

(57 citation statements)

References 26 publications

(33 reference statements)

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“…it is likely that synergistic combinations with other targeted agents are necessary to achieve efficacy that is sufficient for clinical success [43][44][45][46][47][48][49] . We therefore tested carfilzomib and afatinib in combination with each of the 176 selected drugs, at a 10-fold lower dose (1 µM) relative to prior screening assays, in four basal-like PDXs (HCI01, UCD52, WHIM2, WHIM30) (Supplementary File S2).…”

Section: Carfilzomib and Afatinib Have Supra-additive Trends When Commentioning

confidence: 99%

Identification of synergistic drug combinations using breast cancer patient-derived xenografts

Turner

Alzubi

Harrell

2020

Sci Rep

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Compared with other breast cancer subtypes, triple-negative breast cancer (TNBC) is associated with relatively poor outcomes due to its metastatic propensity, frequent failure to respond to chemotherapy, and lack of alternative, targeted treatment options, despite decades of major research efforts. Our studies sought to identify promising targeted therapeutic candidates for TNBC through in vitro screening of 1,363 drugs in patient-derived xenograft (PDX) models. Using this approach, we generated a dataset that can be used to assess and compare responses of various breast cancer PDXs to many different drugs. Through a series of further drug screening assays and two-drug combination testing, we identified that the combination of afatinib (epidermal growth factor receptor (EGFR) inhibitor) and YM155 (inhibitor of baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5; survivin) expression) is synergistically cytotoxic across multiple models of basal-like TNBC and reduces PDX mammary tumor growth in vivo. We found that YM155 reduces EGFR expression in TNBC cells, shedding light on its potential mechanism of synergism with afatinib. Both EGFR and BIRC5 are highly expressed in basallike PDXs, cell lines, and patients, and high expression of both genes reduces metastasis-free survival, suggesting that co-targeting of these proteins holds promise for potential clinical success in TNBC. therefore suitable models for studying tumor biology and drug response, both in vivo and ex vivo/in vitro [22][23][24][25][26][27][28][29][30][31][32][33][34][35] . Using this approach, we have generated a dataset that can be used to quickly assess and compare responses of breast cancer PDXs of varying subtypes to many different drugs, most of which are approved by the U.S. Food and Drug Administration (FDA) for various cancer or non-cancer indications. From these data, we identified 176 drugs that were consistently effective across four basal-like TNBC PDXs, encompassing a wide variety of molecular targets and mechanisms of action. Several of these drugs have shown promising efficacy in TNBC and other solid tumors, however it is likely that incorporation into combination regimens is needed to maximize their efficacy and thus their likelihood of clinical success. Through a series of in vitro drug response assays, we selected four drugs to test in various two-drug combinations: carfilzomib (proteasome inhibitor), afatinib (epidermal growth factor receptor (EGFR) inhibitor), and YM155 (inhibitor of baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5; survivin) expression), along with carboplatin, a chemotherapeutic that is part of the current standard-of-care for TNBC and that we have previously tested in several PDXs 36 . Of the six drug combinations tested, we found that the combination of afatinib and YM155 was synergistically cytotoxic across four basal-like TNBC PDXs, and this drug combination significantly reduced PDX mammary tumor growth in vivo, without observable toxicity. Notably, the genes encoding the targets of ...

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Section: Carfilzomib and Afatinib Have Supra-additive Trends When Commentioning

confidence: 99%

Identification of synergistic drug combinations using breast cancer patient-derived xenografts

Turner

Alzubi

Harrell

2020

Sci Rep

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“…TNBC is biologically aggressive and has the poorest prognosis when compared to other subtypes 3 . Previous study reported that EGFR is a potential target for TNBC 7 . In this work, epigallocatechin and epicatechin metabolites had notable predicted binding affinity towards EGFR kinase domain.…”

Section: Discussionmentioning

confidence: 99%

“…But different from previous subtypes, triple negative breast cancer is not responded very well to hormone treatment and HER2 antibody, and often treated with systemic chemotherapy. Previous study found that epidermal growth factor receptor (EGFR) kinase inhibitor, gefitinib, was able to halt the TNBC cell outgrowth in vitro 7 . Thus ER, HER2, EGFR served as important targets in breast cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Dietary flavonoids against various breast cancer subtypes: a molecular docking study

Widowati¹,

Jasaputra²,

Heriady³

et al. 2019

ScienceAsia

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Breast cancer is female most frequent diagnosed cancer and the leading cause of cancer death. The consumption of dietary flavonoids is reported to cause significant breast cancer risk reduction. In vitro studies often used aglycone flavonoids rather than its conjugated form that actually present in human body. Thus its mechanism against breast cancer has not been elucidated completely. The present study aimed to investigate the possible mechanism of dietary flavonoids against breast cancer by in silico study. Conjugated flavonoids were docked to ER (estrogen receptor), HER2 (human epidermal growth factor receptor 2) and EGFR (epidermal growth factor receptor) kinase domains. The molecular docking of 22 flavonoid conjugates towards EGFR and HER2 kinase domain, and ER was successfully performed. Potential binders to proteins: epicatechin conjugates to ER (−8.7 kcal/mol), isoflavone conjugates to HER2 kinase domain (−10.7 kcal/mol), and epigallocatechin and epicatechin conjugates to EGFR kinase domain (−9.2 kcal/mol), were suggested. Supported by other studies, conjugated flavonoids may exert similar inhibitory and agonistic properties to their parent flavonoids. Taken together, the present study showed possible effects of dietary flavonoids against various breast cancer subtypes.

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“…To that end, particular effort should be taken to carefully characterize the cellular states of preclinical models and understand their relationship to cellular states observed in patients, as different models might recapitulate different tumor compartments, as recently shown in H3 K27M-mutant glioma (Filbin et al 2018). Future work applying similar strategies will interrogate the developmental lineages and putative CSC programs in a range of malignancies (Savage et al 2017). In addition, identification of putative CSCs by scRNA-seq should be followed by functional studies to test the tumor initiation capacity and drug resistance of these subpopulations.…”

Section: Developmental Lineages and Cancer Stem Cellsmentioning

confidence: 99%

Deciphering Human Tumor Biology by Single-Cell Expression Profiling

Tirosh

Suvà

2019

Annu. Rev. Cancer Biol.

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Human tumors are complex ecosystems where diverse cancer and noncancer cells interact to determine tumor biology and response to therapies. Genomic and transcriptomic methods have traditionally profiled these intricate ecosystems as bulk samples, thereby masking individual cellular programs and the variability among them. Recent advances in single-cell profiling have paved the way for studying tumors at the resolution of individual cells, providing a compelling strategy to bridge gaps in our understanding of human tumors. Here, we review methodologies for single-cell expression profiling of tumors and the initial studies deploying them in clinical contexts. We highlight how these studies uncover new biology and provide insights into drug resistance, stem cell programs, metastasis, and tumor classifications. We also discuss areas of technology development in single-cell genomics that provide new tools to address key questions in cancer biology. These emerging studies and technologies have the potential to revolutionize our understanding and management of human malignancies.

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A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer

Cited by 71 publications

References 26 publications

Identification of synergistic drug combinations using breast cancer patient-derived xenografts

Identification of synergistic drug combinations using breast cancer patient-derived xenografts

Dietary flavonoids against various breast cancer subtypes: a molecular docking study

Deciphering Human Tumor Biology by Single-Cell Expression Profiling

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