Drug Resistance in Colorectal Cancer: From Mechanism to Clinic

SIMPLE SUMMARY: Chemotherapy, radiotherapy and molecularly targeted therapy could improve the prognosis of colorectal cancer (CRC) patients. Recently, immunotherapy, especially immune checkpoint inhibitors, has significantly improved the prognosis of some patients. However, drug resistance significantly reduces the usefulness of these drugs. Although research on the molecular mechanisms underlying the emergence of drug resistance is ongoing, the specific molecular mechanisms remain unclear. This article reviews the findings on the mechanisms of drug resistance in CRC patients in preclinical and clinical studies, which may provide valuable directions for future in-depth study of drug resistance. ABSTRACT: Colorectal cancer (CRC) is one of the leading causes of death worldwide. The 5-year survival rate is 90% for patients with early CRC, 70% for patients with locally advanced CRC, and 15% for patients with metastatic CRC (mCRC). In fact, most CRC patients are at an advanced stage at the time of diagnosis. Although chemotherapy, molecularly targeted therapy and immunotherapy have significantly improved patient survival, some patients are initially insensitive to these drugs or initially sensitive but quickly become insensitive, and the emergence of such primary and secondary drug resistance is a significant clinical challenge. The most direct cause of resistance is the aberrant anti-tumor drug metabolism, transportation or target. With more in-depth research, it is found that cell death pathways, carcinogenic signals, compensation feedback loop signal pathways and tumor immune microenvironment also play essential roles in the drug resistance mechanism. Here, we assess the current major mechanisms of CRC resistance and describe potential therapeutic interventions.