Pharmacological inhibition of HSP90 radiosensitizes HNSCC xenograft by inhibition of DNA damage repair, nucleotide metabolism, and radiation-induced tumor vasculogenesis

Sarwat Naz, Andrew J Leiker, Rajani Choudhuri, Olivia Preston, Anastasia L Sowers, Sangeeta Gohain, Janet Gamson, Askale Mathias, Carter Van Waes, John A Cook, James B Mitchell
International Journal of Radiation Oncology, Biology, Physics 2021 April 7

PURPOSE: Recent pre-clinical studies suggest combining the HSP90 inhibitor AT13387 (Onalespib) with radiation (IR) against colon cancer and HNSCC. These studies emphasized that AT13387 down-regulates HSP90 client proteins involved in oncogenic signaling and DNA repair mechanisms as major drivers of enhanced radiosensitivity. Given the large array of client proteins HSP90 directs, we hypothesized that other key proteins or signaling pathways may be inhibited by AT13387 and contribute to enhanced radiosensitivity. Metabolomic analysis of HSP90 inhibition by AT13387 was conducted to identify metabolic biomarkers of radiosensitization and whether modulations of key proteins were involved in IR-induced tumor vasculogenesis, a process involved in tumor recurrence.

METHODS AND MATERIALS: HNSCC and NSCLC cell lines were used to evaluate the AT13387 radiosensitization effect in vitro and in vivo. Flow cytometry, immunofluorescence, and immunoblot analysis were utilized to evaluate cell cycle changes and HSP90 client protein's role in DNA damage repair. Metabolic analysis was performed using LC/MS mass spectrometry. Immunohistochemical examination of resected tumors post-AT13387 and IR treatment were conducted to identify biomarkers of IR-induced tumor vasculogenesis.

RESULTS: In agreement with recent studies, AT13387 treatment combined with IR resulted in a G2/M cell cycle arrest and inhibited DNA repair. Metabolomic profiling indicated a decrease in key metabolites in glycolysis and TCA cycle by AT13387, reduction in ATP levels, and rate-limiting metabolites in nucleotide metabolism, namely PRPP and aspartate. HNSCC xenografts treated with the combination exhibited increased tumor regrowth delay, decreased tumor infiltration of CD45 and CD11b+ bone marrow derived cells and inhibition of HIF-1 and SDF-1 expression thereby inhibiting IR-induced vasculogenesis.

CONCLUSIONS: AT13387 treatment resulted in pharmacological inhibition of cancer cell metabolism that was linked to DNA damage repair. AT13387 combined with IR inhibited IR-induced vasculogenesis, a process involved in tumor recurrence postradiotherapy. Combining AT13387 with IR warrants consideration of clinical trial assessment.

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