Redefining Therapeutic Approaches in Colorectal Cancer: Targeting Molecular Pathways and Overcoming Resistance

Abstract

Colorectal cancer (CRC) arises through a combination of genetic and epigenetic alterations that affect key pathways involved in tumor growth and progression. This review examines the major molecular pathways driving CRC, including Chromosomal Instability (CIN), Microsatellite Instability (MSI), and the CpG Island Methylator Phenotype (CIMP). Key mutations in genes such as APC, KRAS, NRAS, BRAF, and TP53 activate signaling pathways like Wnt, EGFR, and PI3K/AKT, contributing to tumorigenesis and influencing responses to targeted therapies. Resistance mechanisms, including mutations that bypass drug action, remain challenging in CRC treatment. This review highlights the role of molecular profiling in guiding the use of targeted therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitors. Novel combination treatments are also discussed as strategies to improve outcomes and overcome resistance. Understanding these molecular mechanisms is critical to advancing personalized treatment approaches in CRC and improving patient prognosis.

Keywords: APC pathway; BRAF mutations; KRAS mutations; MSI/dMMR; PI3K/AKT/mTOR pathway; colon cancer; immunotherapy; targeted therapy.

Figure 1

The three major molecular pathways in CRC carcinogenesis.

Figure 2

Inhibition points in the major molecular pathways and targeted treatment options.

Figure 3

Mechanism of action of current checkpoint inhibitors in CRC.