HSP90 inhibition suppresses tumor glycolytic flux to potentiate the therapeutic efficacy of radiotherapy for head and neck cancer
Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons tumoraux issus de patients atteints d'un carcinome épidermoïde de la tête et du cou, cette étude démontre que l'inhibition de la protéine HSP90 potentialise l'efficacité de la radiothérapie en supprimant le flux glycolitique de la tumeur
Glycolytic metabolism may account for antitumor immunity failure. Pyruvate kinase M2 (PKM2) and platelet phosphofructokinase (PFKP), two key enzymes involved in the glycolytic pathway, are hyperactivated in head and neck squamous cell carcinoma (HNSCC). Using ganetespib as a drug model for heat shock protein 90 (HSP90) inhibition and combining results from clinical trials and animal treatment, we demonstrated that HSP90 inhibition leads to a blockade of glycolytic flux in HNSCC cells by simultaneously suppressing PKM2 and PFKP at both the transcriptional and posttranslational levels. Down-regulation of tumor glycolysis facilitates tumor infiltration of cytotoxic T cells via suppression of glycolysis-dependent interleukin-8 signaling. The addition of ganetespib to radiation attenuates radiation-induced up-regulation of PKM2 and PFKP and potentiates T cell–mediated antitumor immunity, resulting in a more potent antitumor effect than either treatment alone, providing a molecular basis for exploring the combination of HSP90 inhibitors with radiotherapy to improve outcomes for patients with HNSCC. Ganetespib’s suppression of tumor glycolytic flux provides rationale for combination with radiotherapy.
Science Advances , article en libre accès, 2023