KLF5 inhibition overcomes oxaliplatin resistance in patient-derived colorectal cancer organoids by restoring apoptotic response

Abstract Background: Oxaliplatin resistance is a major challenge for treatment of metastatic colorectal cancer (mCRC). Many molecular targeted drugs for refractory CRC have been developed to solve colorectal cancer drug resistance, but their effectiveness and roles in the progression of CRC and oxaliplatin- resistance still not clear.Methods: PDOs derived from CRC patients were constructed to conduct the sensitivity assays of oxaliplatin in vitro. Oxaliplatin resistant PDOs were selected and treated under the combined treatment of ML264(a KLF5 inhibitor) and oxaliplatin to determine the effects of KLF5 inhibition on apoptosis. Using CRC cell lines to investigate downstream mechanisms and xenograft models to confirm whether ML264 can restore oxaliplatin sensitivity of CRC cells in vivo.Results: We successfully constructed CRC PDOs and conducted the sensitivity test of oxaliplatin in PDOs from different patients. We found that ML264 restores oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response, and this effect was achieved by inhibiting the KLF5/Bcl-2/caspase3 signal pathway. Chromatin immunoprecipitation (ChIP) and luciferase reporter assay verified that KLF5 promoted the transcription of Bcl-2 in CRC cells. KLF5 inhibition also overcomed oxaliplatin resistance in xenograft tumors.Conclusions: Our study demonstrated that ML264 can restores oxaliplatin sensitivity in CRC PDOs by restoring the apoptotic response. KLF5 might be a potential therapeutic target for CRC resistant to oxaliplatin. PDOs have strong potential in evaluating inhibitors and drug combinations therapy in a preclinical environment.