Colorectal cancer (CRC) is a complex disease with multiple molecular mechanisms driving its development and progression. Based on PubMed publications over the past three years, several key mechanisms of action (MoAs) have emerged as important in CRC:

• Genetic and Epigenetic Alterations:

• Mutations: Mutations in key driver genes like APC, KRAS, BRAF, PIK3CA, SMAD4, and TP53 are frequently observed in CRC and play significant roles in tumor initiation, progression, and metastasis. KRAS and TP53 mutations are particularly associated with metastasis, while BRAF mutations are linked to metastasis in Asian populations. APC and PIK3CA mutations have shown less consistent associations with metastasis. Other important mutations include those affecting DNA mismatch repair genes, leading to microsatellite instability (MSI), and mutations in genes involved in the chromosomal instability (CIN) pathway.

• Epigenetic Changes: Aberrant DNA methylation, microRNA (miRNA) deregulation, and alterations in histone modification states are common in CRC and contribute to gene dysregulation and tumor development.

• Genomic Instability: CIN, characterized by chromosomal gains and losses, and MSI, marked by insertions or deletions at repetitive DNA sequences, are two major pathways involved in CRC development. MSI is associated with a better prognosis and response to immunotherapy.

• Dysregulated Signaling Pathways:

• WNT Signaling: The Wnt signaling pathway is crucial for regulating cell growth and differentiation. Mutations in APC and other Wnt pathway components lead to constitutive activation of the pathway, driving CRC development.

• MAPK/ERK Signaling: The MAPK/ERK pathway is involved in cell proliferation and survival. Mutations in KRAS and BRAF activate this pathway, contributing to CRC progression.

• PI3K/Akt/mTOR Signaling: This pathway regulates cell growth, metabolism, and survival. Mutations in PIK3CA and PTEN dysregulate this pathway, promoting CRC development and drug resistance.

• TGF- Signaling: TGF- normally inhibits cell growth, but its signaling is often disrupted in CRC, leading to tumor progression.

• TP53 Pathway: The TP53 tumor suppressor gene plays a crucial role in cell cycle regulation and apoptosis. TP53 mutations impair its function, contributing to CRC development.

• STAT3 Signaling: STAT3 is a transcription factor involved in inflammation and cell growth. Its hyperactivation in CRC promotes tumor progression and immune evasion.

• Tumor Microenvironment:

• Immune Cells: The tumor microenvironment in CRC is often immunosuppressive, with infiltration of M2-like macrophages and other immune cells that promote tumor growth and metastasis. Neoadjuvant chemotherapy can modulate the immune microenvironment and restore antitumor immunity in some patients.

• Stromal Cells: Cancer-associated fibroblasts and other stromal cells in the TME interact with CRC cells and contribute to tumor progression.

• Gut Microbiota: Dysbiosis of the gut microbiota is implicated in CRC development. Specific bacteria, such as Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis, have been linked to CRC initiation and progression. The gut microbiome can also influence the response to CRC therapies.

• Metabolic Reprogramming:

• CRC cells undergo metabolic reprogramming to support their rapid proliferation. This includes increased glycolysis, glutaminolysis, one-carbon metabolism, and fatty acid synthesis. Metabolic changes can vary within tumors and are influenced by the TME and gut microbiota.

Understanding these MoAs is crucial for developing targeted therapies and improving patient outcomes in CRC. Ongoing research continues to unravel the complex interplay of these mechanisms and identify new therapeutic targets.