Cell cycle progression and
DNA synthesis are essential steps in
cancer cell growth.
Thymidylate synthase (TS) is a therapeutic target for
5FU. We tested the hypothesis that HSP90 transcriptional and functional inhibition can inhibit cell cycle progression, downregulate TS levels and sensitize
colorectal cancer (CRC) cell lines to the effects of
5FU. Treatment with
ganetespib (50 nM) for 24 hours inhibited
cyclin D1 and pRb at the transcriptional and translational levels and induced p21, leading to G0/G1 cell cycle arrest in both CRC cell lines (HCT-116 and HT-29). This was associated with downregulation of E2F1 and its target gene TS. In addition,
ganetespib inhibited PI3K/Akt and ERK signalling pathways. Similar effects were observed with HSP90 knockdown in both cell lines.
Ganetespib sensitized CRC cell lines to the effects of
oxaliplatin and
5FU. Similar effects were also observed in
tumors from animals treated with
ganetespib,
oxaliplatin and
5FU. In this study, we present in vitro and animal data supporting that the targeting of HSP90 decreases CRC cell survival and proliferation.
Ganetespib sensitizes CRC cell lines to the effects of 5FU-based
chemotherapy. Combining HSP90 inhibitors with
chemotherapy is a rational approach for future drug development in CRC.