Abstract B103: HSP90 inhibition targets the dysregulated signal and transcription factor network and malignant phenotype of head and neck squamous cell carcinoma.

Purpose: Activation of multiple oncogenic signaling pathways and transcription factors, concurrent with defective tumor suppressor TP53, have been implicated in pathogenesis and therapeutic resistance of epithelial cancers. Many proteins upon which these cancers depend are stabilized by the chaperone, heat shock protein 90 (HSP90). Here we characterized the effects of HSP90 inhibitor, PF-04928473, against the dysregulated network and malignant phenotype in head and neck squamous cell carcinoma (HNSCC).

Experimental Design: HSP90 expression was analyzed in HNSCC tissue array and cell lines. Expression and function of oncogenic molecules and cytokines were analyzed by Western blot, reporter gene, and multiplex Luminex assays. Drug effects on proliferation, cell cycle, and radiosensitivity were evaluated by MTT, flow cytometry, and clonogenic assays. Anti-tumor effects and modulation of immunohistochemical markers were evaluated in a TP53-deficient xenograft model resistant to targeted therapies.

Results: HNSCC tissues and lines overexpressed HSP90. PF-04928473 inhibited dysregulated EGFR, c-MET, AKT, ERK1/2, IKK signal molecules, AP-1, STAT3, and NF-B reporter genes, and expression of target oncogenes and angiogenic cytokines. PF-04928473 induced re-expression of TP53 and targets p21 and PUMA in TP53-deficient HNSCC. Corresponding to effects on these molecules implicated in HNSCC pathogenesis, PF-04928473 inhibited proliferation, induced G2/M block, apoptosis, and enhanced radiosensitivity in vitro. PF-04928473 similarly modulated key targets, inducing apoptosis, and inhibiting proliferation, angiogenesis and xenograft tumorigenesis in vivo.

Conclusion: HSP90 antagonist PF-04928473 modulated the dysregulated signal and transcriptional network, inhibited the malignant phenotype, and radiosensitized HNSCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B103.