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Activation of the EGFR/PI3K/AKT pathway limits the efficacy of trametinib treatment in head and neck cancer

Blocking the mitogen-activated protein kinase (MAPK) pathway with the MEK1/2 inhibitor trametinib has produced promising results in patients with head and neck squamous cell carcinoma (HNSCC). In the current study, we showed that trametinib treatment leads to overexpression and activation of the epi...

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Hauptverfasser: Novoplansky, Ofra (VerfasserIn) , Shnerb, Avital B. (VerfasserIn) , Marripati, Divyasree (VerfasserIn) , Jagadeeshan, Sankar (VerfasserIn) , Abu Shareb, Raghda (VerfasserIn) , Conde-Lopez, Cristina (VerfasserIn) , Zorea, Jonathan (VerfasserIn) , Prasad, Manu (VerfasserIn) , Ben Lulu, Talal (VerfasserIn) , Yegodayev, Ksenia M. (VerfasserIn) , Benafsha, Chen (VerfasserIn) , Li, Yushi (VerfasserIn) , Kong, Dexin (VerfasserIn) , Kuo, Fengshen (VerfasserIn) , Morris, Luc G. T. (VerfasserIn) , Kurth, Ina (VerfasserIn) , Heß, Jochen (VerfasserIn) , Elkabets, Moshe (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 27 July 2023
Ausgabe:Online version of record before inclusion in an issue
In: Molecular oncology
Year: 2023, Jahrgang: 17, Heft: 12, Pages: 2618-2636
ISSN:1878-0261
DOI:10.1002/1878-0261.13500
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/1878-0261.13500
Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/1878-0261.13500
Volltext
Verfasserangaben:Ofra Novoplansky, Avital B. Shnerb, Divyasree Marripati, Sankar Jagadeeshan, Raghda Abu Shareb, Cristina Conde-López, Jonathan Zorea, Manu Prasad, Talal Ben Lulu, Ksenia M. Yegodayev, Chen Benafsha, Yushi Li, Dexin Kong, Fengshen Kuo, Luc G.T. Morris, Ina Kurth, Jochen Hess and Moshe Elkabets
Beschreibung
Zusammenfassung:Blocking the mitogen-activated protein kinase (MAPK) pathway with the MEK1/2 inhibitor trametinib has produced promising results in patients with head and neck squamous cell carcinoma (HNSCC). In the current study, we showed that trametinib treatment leads to overexpression and activation of the epidermal growth factor receptor (EGFR) in HNSCC cell lines and patient-derived xenografts. Knockdown of EGFR improved trametinib treatment efficacy both in vitro and in vivo. Mechanistically, we demonstrated that trametinib-induced EGFR overexpression hyperactivates the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. In vitro, blocking the PI3K pathway with GDC-0941 (pictilisib), or BYL719 (alpelisib), prevented AKT pathway hyperactivation and enhanced the efficacy of trametinib in a synergistic manner. In vivo, a combination of trametinib and BYL719 showed superior antitumor efficacy vs. the single agents, leading to tumor growth arrest. We confirmed our findings in a syngeneic murine head and neck cancer cell line in vitro and in vivo. Taken together, our findings show that trametinib treatment induces hyperactivation of EGFR/PI3K/AKT; thus, blocking of the EGFR/PI3K pathway is required to improve trametinib efficacy in HNSCC.
Beschreibung:Gesehen am 14.11.2023
Beschreibung:Online Resource
ISSN:1878-0261
DOI:10.1002/1878-0261.13500

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