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EGFR and PI3K Signalling Pathways as Promising Targets on Circulating Tumour Cells from Patients with Metastatic Gastric Adenocarcinoma

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EGFR and PI3K Signalling Pathways as Promising Targets on Circulating Tumour Cells from Patients with Metastatic Gastric Adenocarcinoma. / Piper, Ann-Katrin; Penney, Chelsea; Holliday, Jacqueline; Tincknell, Gary; Ma, Yafeng; Napaki, Sarbar; Pantel, Klaus; Brungs, Daniel; Ranson, Marie.

in: INT J MOL SCI, Jahrgang 25, Nr. 10, 5565, 20.05.2024.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Piper, A-K, Penney, C, Holliday, J, Tincknell, G, Ma, Y, Napaki, S, Pantel, K, Brungs, D & Ranson, M 2024, 'EGFR and PI3K Signalling Pathways as Promising Targets on Circulating Tumour Cells from Patients with Metastatic Gastric Adenocarcinoma', INT J MOL SCI, Jg. 25, Nr. 10, 5565. https://doi.org/10.3390/ijms25105565

APA

Piper, A-K., Penney, C., Holliday, J., Tincknell, G., Ma, Y., Napaki, S., Pantel, K., Brungs, D., & Ranson, M. (2024). EGFR and PI3K Signalling Pathways as Promising Targets on Circulating Tumour Cells from Patients with Metastatic Gastric Adenocarcinoma. INT J MOL SCI, 25(10), [5565]. https://doi.org/10.3390/ijms25105565

Vancouver

Piper A-K, Penney C, Holliday J, Tincknell G, Ma Y, Napaki S et al. EGFR and PI3K Signalling Pathways as Promising Targets on Circulating Tumour Cells from Patients with Metastatic Gastric Adenocarcinoma. INT J MOL SCI. 2024 Mai 20;25(10). 5565. https://doi.org/10.3390/ijms25105565

Bibtex

@article{c0c6c788bd4b4a70aeea9395ad927c87,
title = "EGFR and PI3K Signalling Pathways as Promising Targets on Circulating Tumour Cells from Patients with Metastatic Gastric Adenocarcinoma",
abstract = "The prognosis for metastatic gastric adenocarcinoma (mGAC) remains poor. Gene alterations in receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR) and their downstream effectors including catalytic subunit alpha of the phosphatidylinositol 3-kinase (PIK3CA) are common in mGAC. Targeted RTK and phosphatidylinositol-3-kinase (PI3K) treatments have demonstrated clinical benefits in other solid tumours and are key potential targets for clinical development against mGAC given the presence of recurrent alterations in these pathways. Furthermore, combination RTK/PI3K treatments may overcome compensatory mechanisms that arise using monotherapies, leading to improved patient outcomes. Herein, we investigated RTK/PI3K single and combination drug responses against our unique human mGAC-derived PIK3CA gain-of-function mutant, human epidermal growth factor receptor 2 (HER2)-negative, EGFR-expressing circulating tumour cell line, UWG02CTC, under two- and three-dimensional culture conditions to model different stages of metastasis. UWG02CTCs were highly responsive to the PI3K p110α-subunit targeted drugs PIK-75 (IC50 = 37.0 ± 11.1 nM) or alpelisib (7.05 ± 3.7 µM). Drug sensitivities were significantly increased in 3D conditions. Compensatory MAPK/ERK pathway upregulation by PI3K/Akt suppression was overcome by combination treatment with the EGFR inhibitor gefitinib, which was strongly synergistic. PIK-75 plus gefitinib significantly impaired UWG02CTC invasion in an organotypic assay. In conclusion, UWG02CTCs are a powerful ex vivo mGAC drug responsiveness model revealing EGFR/PI3K-targeted drugs as a promising combination treatment option for HER2-negative, RAS wild-type mGAC patients.",
keywords = "Humans, Stomach Neoplasms/pathology, ErbB Receptors/metabolism, Signal Transduction/drug effects, Adenocarcinoma/drug therapy, Cell Line, Tumor, Class I Phosphatidylinositol 3-Kinases/metabolism, Neoplastic Cells, Circulating/metabolism, Phosphatidylinositol 3-Kinases/metabolism, Neoplasm Metastasis, Phosphoinositide-3 Kinase Inhibitors/pharmacology, Protein Kinase Inhibitors/pharmacology, Antineoplastic Agents/pharmacology, Thiazoles",
author = "Ann-Katrin Piper and Chelsea Penney and Jacqueline Holliday and Gary Tincknell and Yafeng Ma and Sarbar Napaki and Klaus Pantel and Daniel Brungs and Marie Ranson",
year = "2024",
month = may,
day = "20",
doi = "10.3390/ijms25105565",
language = "English",
volume = "25",
journal = "INT J MOL SCI",
issn = "1661-6596",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "10",

}

RIS

TY - JOUR

T1 - EGFR and PI3K Signalling Pathways as Promising Targets on Circulating Tumour Cells from Patients with Metastatic Gastric Adenocarcinoma

AU - Piper, Ann-Katrin

AU - Penney, Chelsea

AU - Holliday, Jacqueline

AU - Tincknell, Gary

AU - Ma, Yafeng

AU - Napaki, Sarbar

AU - Pantel, Klaus

AU - Brungs, Daniel

AU - Ranson, Marie

PY - 2024/5/20

Y1 - 2024/5/20

N2 - The prognosis for metastatic gastric adenocarcinoma (mGAC) remains poor. Gene alterations in receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR) and their downstream effectors including catalytic subunit alpha of the phosphatidylinositol 3-kinase (PIK3CA) are common in mGAC. Targeted RTK and phosphatidylinositol-3-kinase (PI3K) treatments have demonstrated clinical benefits in other solid tumours and are key potential targets for clinical development against mGAC given the presence of recurrent alterations in these pathways. Furthermore, combination RTK/PI3K treatments may overcome compensatory mechanisms that arise using monotherapies, leading to improved patient outcomes. Herein, we investigated RTK/PI3K single and combination drug responses against our unique human mGAC-derived PIK3CA gain-of-function mutant, human epidermal growth factor receptor 2 (HER2)-negative, EGFR-expressing circulating tumour cell line, UWG02CTC, under two- and three-dimensional culture conditions to model different stages of metastasis. UWG02CTCs were highly responsive to the PI3K p110α-subunit targeted drugs PIK-75 (IC50 = 37.0 ± 11.1 nM) or alpelisib (7.05 ± 3.7 µM). Drug sensitivities were significantly increased in 3D conditions. Compensatory MAPK/ERK pathway upregulation by PI3K/Akt suppression was overcome by combination treatment with the EGFR inhibitor gefitinib, which was strongly synergistic. PIK-75 plus gefitinib significantly impaired UWG02CTC invasion in an organotypic assay. In conclusion, UWG02CTCs are a powerful ex vivo mGAC drug responsiveness model revealing EGFR/PI3K-targeted drugs as a promising combination treatment option for HER2-negative, RAS wild-type mGAC patients.

AB - The prognosis for metastatic gastric adenocarcinoma (mGAC) remains poor. Gene alterations in receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR) and their downstream effectors including catalytic subunit alpha of the phosphatidylinositol 3-kinase (PIK3CA) are common in mGAC. Targeted RTK and phosphatidylinositol-3-kinase (PI3K) treatments have demonstrated clinical benefits in other solid tumours and are key potential targets for clinical development against mGAC given the presence of recurrent alterations in these pathways. Furthermore, combination RTK/PI3K treatments may overcome compensatory mechanisms that arise using monotherapies, leading to improved patient outcomes. Herein, we investigated RTK/PI3K single and combination drug responses against our unique human mGAC-derived PIK3CA gain-of-function mutant, human epidermal growth factor receptor 2 (HER2)-negative, EGFR-expressing circulating tumour cell line, UWG02CTC, under two- and three-dimensional culture conditions to model different stages of metastasis. UWG02CTCs were highly responsive to the PI3K p110α-subunit targeted drugs PIK-75 (IC50 = 37.0 ± 11.1 nM) or alpelisib (7.05 ± 3.7 µM). Drug sensitivities were significantly increased in 3D conditions. Compensatory MAPK/ERK pathway upregulation by PI3K/Akt suppression was overcome by combination treatment with the EGFR inhibitor gefitinib, which was strongly synergistic. PIK-75 plus gefitinib significantly impaired UWG02CTC invasion in an organotypic assay. In conclusion, UWG02CTCs are a powerful ex vivo mGAC drug responsiveness model revealing EGFR/PI3K-targeted drugs as a promising combination treatment option for HER2-negative, RAS wild-type mGAC patients.

KW - Humans

KW - Stomach Neoplasms/pathology

KW - ErbB Receptors/metabolism

KW - Signal Transduction/drug effects

KW - Adenocarcinoma/drug therapy

KW - Cell Line, Tumor

KW - Class I Phosphatidylinositol 3-Kinases/metabolism

KW - Neoplastic Cells, Circulating/metabolism

KW - Phosphatidylinositol 3-Kinases/metabolism

KW - Neoplasm Metastasis

KW - Phosphoinositide-3 Kinase Inhibitors/pharmacology

KW - Protein Kinase Inhibitors/pharmacology

KW - Antineoplastic Agents/pharmacology

KW - Thiazoles

U2 - 10.3390/ijms25105565

DO - 10.3390/ijms25105565

M3 - SCORING: Journal article

C2 - 38791602

VL - 25

JO - INT J MOL SCI

JF - INT J MOL SCI

SN - 1661-6596

IS - 10

M1 - 5565

ER -