2. Academic Validation
  3. Activation of the EGFR/PI3K/AKT pathway limits the efficacy of trametinib treatment in head and neck cancer

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

  • Mol Oncol. 2023 Jul 27. doi: 10.1002/1878-0261.13500.
Ofra Novoplansky 1,  Avital B Shnerb 1,  Divyasree Marripati 1,  Sankar Jagadeeshan 1,  Raghda Abu Shareb 1,  Cristina Conde-López 2,  Jonathan Zorea 1,  Manu Prasad 1,  Talal Ben Lulu 1,  Ksenia M Yegodayev 1,  Chen Benafsha 3,  Yushi Li 4,  Dexin Kong 5,  Fengshen Kuo 6,  Luc G T Morris 6,  Ina Kurth 2,  Jochen Hess 7 8,  Moshe Elkabets 1
Affiliations

Affiliations

  • 1 The Shraga Segal Department of Microbiology, Immunology, and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
  • 2 Division of Radiooncology-Radiobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 3 Department of Chemical Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
  • 4 Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, United Kingdom.
  • 5 School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin, China.
  • 6 Immunogenomics and Precision Oncology Platform, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 7 Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany.
  • 8 Research Group Molecular Mechanisms of Head and Neck Tumors, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
PMID: 37501404 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.

Keywords

PI3K and EGFR signaling; Trametinib; drug resistance; head and neck cancer.

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