HSP90 Inhibition Enhances the Anti-Tumor Efficacy of Combination Chemo Immunotherapy Targeting DNA Repair Proteins

Although melanoma is generally considered to be resistant to genotoxic chemotherapeutic agents such as temozolomide (TMZ), we report that treatment of human and murine melanoma cell lines with TMZ up regulates their expression of DNA repair proteins (DNA-RP) known to be stabilized by the molecular chaperone HSP90.Such TMZ-induced changes in DNA-RP expression were observed in vitro, as well as in vivo, in the B16 melanoma model.Based on our previous studies focused on the tumor-associated HSP90 client protein EphA2 (a cell surface receptor tyrosine kinase), we hypothesized that TMZinduced DNA-RP might serve as substrates for the generation of MHC class I-presented peptide epitopes upon administration of the HSP90 inhibitor STA9090 (ganetespib).Notably, STA9090 promoted the degradation of TMZ-induced DNA-RP in melanoma cell lines in vitro, and the pre-conditioning of progressively growing B16 melanomas in C57BL/6 mice with systemic TMZ + STA9090 treatment was found to sensitize melanoma cells to the anti-tumor action of adoptively-transferred DNA-RP-specific CD8 + T cells.The anti-tumor efficacy of chemo immunotherapy combining TMZ, STA9090 and antigenspecific adoptive T cell transfer was found to be associated with superior levels of Type-1 CD8 + tumor-infiltrating lymphocytes (TIL) in treated mice and more expansive areas of tissue apoptosis within the tumor microenvironment (TME).These data suggest possible translation of such combination chemo immunotherapy strategies into the clinic for the treatment of patients with melanoma or other forms of cancer.