Chapter Two - Mechanisms of treatment resistance in colorectal cancer

Abstract

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second dominant cause of cancer-related death worldwide. Surgery, radiotherapy, and chemotherapy form the standard of treatment in CRC. Treatment resistance, particularly drug therapy resistance, is one major challenge in the management of the disease. The commonly used chemotherapeutic agents in CRC are 5-fluorouracil, oxaliplatin, and irinotecan. Mechanisms of treatment resistance are multifactorial; however, this can be categorized into intrinsic and acquired forms of resistance. Intrinsic resistance is postulated to fundamental genetic mutations, altered signaling pathways, and tumor heterogeneity which inactivate cancer drugs. Acquired drug resistance develops during treatment with the development of added proto-oncogenes, mutations in the targeted genes, and alterations in the TME. The high mutation burden, rapid cell division, and brisk metastatic capacity of tumor cells also lead to drug resistance. The gut microbiome, miRNA, certain lncRNAs, and splicing changes can influence the evolution of the resistance cell population. Combination therapy with careful avoidance of toxicity is crucial in averting treatment resistance in CRC. Innovative drug delivery mechanisms, such as nanoparticles, have been explored for use in tumors. The potential role of artificial intelligence (AI) in enhancing treatment outcomes and understanding drug resistance in CRC is also taking shape. A vast amount of ongoing research and clinical trials aim to refine the approaches for improved outcomes in CRC.