Journal Article

DKFZ-2023-01518

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Activation of the EGFR/PI3K/AKT pathway limits the efficacy of trametinib treatment in head and neck cancer.

Novoplansky, O. ; Shnerb, A. B. ; Marripati, D. ; Jagadeeshan, S. ; Shareb, R. A. ; Conde-López, C.DKFZ* ; Zorea, J. ; Prasad, M. ; Lulu, T. B. ; Yegodayev, K. M. ; Benafsha, C. ; Li, Y. ; Kong, D. ; Kuo, F. ; Morris, L. G. T. ; Kurth, I.DKFZ* ; Hess, J.DKFZ* ; Elkabets, M.

2023
John Wiley & Sons, Inc. Hoboken, NJ

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Please use a persistent id in citations: doi:10.1002/1878-0261.13500

Abstract: 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 anti-tumor 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.

Keyword(s): PI3K and EGFR signaling ; Trametinib ; drug resistance ; head and neck cancer

Note: 2023 Dec;17(12):2618-2636 / #DKFZ-MOST-Ca204#

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Contributing Institute(s):

1. E220 Radioonkologie Radiobiologie (E220)
2. Molekulare Grundlagen von HNO-Tumoren (E221)

Research Program(s):

1. 315 - Bildgebung und Radioonkologie (POF4-315) (POF4-315)

Appears in the scientific report 2023

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