Cellular response to cetuximab in PTEN-silenced head and neck squamous cell carcinoma cell line.
The implication of loss of PTEN expression in resistance to targeted therapy has already been described in many tumor types. The absence of response to anti-EGFR agents in PTEN-deficient tumors relies on persistent activation of signaling pathways downstream of pEGFR. To investigate the role of PTEN loss of expression in head and neck squamous cell carcinoma (HNSCC) response to cetuximab, we used siRNA in Cal 27 cells and then evaluated key signaling protein activation (pAKT and pERK 1/2) as well as cell viability and proliferation. PTEN silencing in Cal 27 cells led to a constitutive activation of signaling pathways evidenced by a strong increase in pAKT and pERK 1/2 expression. Moreover, PTEN-silenced cells did not show any significant changes either in cell viability or proliferation, only slight modifications on cell cycle. Additionally and unpredictably, our results indicated that PTEN silencing, led to a drastic reduction in pEGFR expression whereas total EGFR level did not significantly vary. Strikingly, despite this overactivation of signaling pathways ruling cell survival and proliferation in siPTEN cells, cetuximab fully exerted pAKT and pERK 1/2 inhibition of expression, similarly to its effect in untransfected Cal 27 cells. In conclusion, our study established that in Cal 27 cells, cetuximab keeps full ability to inhibit EGFR-dependent mechanisms, as shown by a decreased pAKT and pERK 1/2 level of expression, despite a strong PTEN silencing-induced overactivation. In Cal 27 cells, loss of PTEN expression does not lead to a loss of cetuximab efficacy in inhibiting EGFR-downstream signaling pathways, contrarily to data shown in previous works conducted in other tumor types.
EA 4421 SiGReTO Signalisation, Genomique et Recherche Translationnelle en Oncologie, UHP-Nancy 1, Nancy-Universite, 54505 Vandoeuvre-les-Nancy, France.
Jihane
J
Mriouah
Cedric
C
Boura
Sophie
S
Pinel
Anne-Sophie
AS
Chretien
Alexandre
A
Fifre
Jean-Louis
JL
Merlin
Beatrice
B
Faivre
D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000969:Antinematodal Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000068818:Cetuximab; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D018307:Neoplasms, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics*; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D000077195:Squamous Cell Carcinoma of Head and Neck; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000969:Antinematodal Agents; D014408:Biomarkers, Tumor; D034741:RNA, Small Interfering; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000068818:Cetuximab