TY - JOUR
T1 - Activation of the EGFR/PI3K/AKT pathway limits the efficacy of trametinib treatment in head and neck cancer
AU - Novoplansky, Ofra
AU - Shnerb, Avital B.
AU - Marripati, Divyasree
AU - Jagadeeshan, Sankar
AU - Abu Shareb, Raghda
AU - Conde-López, Cristina
AU - Zorea, Jonathan
AU - Prasad, Manu
AU - Ben Lulu, Talal
AU - Yegodayev, Ksenia M.
AU - Benafsha, Chen
AU - Li, Yushi
AU - Kong, Dexin
AU - Kuo, Fengshen
AU - Morris, Luc G.T.
AU - Kurth, Ina
AU - Hess, Jochen
AU - Elkabets, Moshe
N1 - Publisher Copyright:
© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
PY - 2023/12/1
Y1 - 2023/12/1
N2 - 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.
AB - 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.
KW - PI3K and EGFR signaling
KW - Trametinib
KW - drug resistance
KW - head and neck cancer
UR - http://www.scopus.com/inward/record.url?scp=85169327906&partnerID=8YFLogxK
U2 - 10.1002/1878-0261.13500
DO - 10.1002/1878-0261.13500
M3 - Article
C2 - 37501404
AN - SCOPUS:85169327906
SN - 1574-7891
VL - 17
SP - 2618
EP - 2636
JO - Molecular Oncology
JF - Molecular Oncology
IS - 12
ER -
