Mismatch Repair Status in Patient-Derived Colorectal Cancer Organoids Does Not Affect Intrinsic Tumor Cell Sensitivity to Systemic Therapy

SIMPLE SUMMARY: The large majority of patients with metastatic colorectal cancer (mCRC) receive chemotherapy with or without targeted therapy. Tumors with a deficient DNA mismatch repair (dMMR) system respond poorly to systemic therapy and are associated with poor prognosis. However, it is unclear whether dMMR causes therapy resistance in a tumor cell-intrinsic manner, or whether other mechanisms underlie this association. We address this issue by exposing a panel of MMR-deficient and -proficient Patient-Derived Organoids (PDOs) to a series of clinically relevant drugs. We show that MMR status did not correlate with the response of PDOs to any of the drugs tested. By contrast, the presence of activating mutations in the KRAS and BRAF oncogenes was significantly associated with resistance to chemotherapy and sensitivity to drugs targeting oncogene-activated pathways. We conclude that tumor cell-intrinsic signals link oncogene status, but not MMR status, to variation in therapy response in CRC. ABSTRACT: DNA mismatch repair deficiency (dMMR) in metastatic colorectal cancer (mCRC) is associated with poor survival and a poor response to systemic treatment. However, it is unclear whether dMMR results in a tumor cell-intrinsic state of treatment resistance, or whether alternative mechanisms play a role. To address this, we generated a cohort of MMR-proficient and -deficient Patient-Derived Organoids (PDOs) and tested their response to commonly used drugs in the treatment of mCRC, including 5-fluorouracil (5-FU), oxaliplatin, SN-38, binimetinib, encorafenib, and cetuximab. MMR status did not correlate with the response of PDOs to any of the drugs tested. In contrast, the presence of activating mutations in the KRAS and BRAF oncogenes was significantly associated with resistance to chemotherapy and sensitivity to drugs targeting oncogene-activated pathways. We conclude that mutant KRAS and BRAF impact the intrinsic sensitivity of tumor cells to chemotherapy and targeted therapy. By contrast, tumor cell-extrinsic mechanisms—for instance signals derived from the microenvironment—must underlie the association of MMR status with therapy response. Future drug screens on rationally chosen cohorts of PDOs have great potential in developing tailored therapies for specific CRC subtypes including, but not restricted to, those defined by BRAF/KRAS and MMR status.