Introduction: Unfortunately, metastatic colorectal cancer (mCRC) remains a significant challenge as the third leading cause of cancer-related death. For patients with mCRC, a combination of surgery, systemic therapy, and/or locoregional therapy are currently applied. However, five-year survival for CRC patients with advanced disease remains poor (10–30%). According to the individual genetic profile signature and variation biology of different subtypes of CRC, 20% of CRC patients reported the manifestation of synchronous metastases, and another 40% who present with locoregional disease will show metastatic disease. Heterogenicity in the tumorigenesis process of CRC is the leading cause of unpredictable behavior and prognosis of the disease.
Methods: The epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and DNA mismatch repair pathways have shown promising results for targeted therapies. In addition, discovering new gene mutations and proteins that participated in the oncogenesis of mCRC provides an opportunity for more investigations related to novel therapeutic approaches.
Results: One of the FDA Approved targeted therapies for mCRC are EGFR inhibitors, including Cetuximab and Panitumumab that stimulate downstream pathways of RAS/RAF/MEK/ERK, PI3K/AKT, and JAK/STAT3. In addition, Encorafenib is a BRAF inhibitor. Overexpression of proteins in these pathways results in cell growth, proliferation, and carcinogenesis. Second, VEGF inhibitors, including Bevacizumab, Ramucirumab, Aflibercept, and Fruquintinib. Overexpression of VEGFs increases the formation of blood vessels and promotes angiogenesis and subsequent proliferation. Third, human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase protein with the proto-oncogenic role that is encoded by the ERBB2 gene. It is estimated that 3–5% of CRCs amplificated HER2. In this way, Trastuzumab, Pertuzumab, and Tucatinib are HER2 inhibitors that can be applied as a therapeutic approach in CRC patients with HER2 amplification. Fourth, 15% of CRC tumors are presented by microsatellite instability (MSI) that defects DNA mismatch repair. Some immune checkpoint inhibitors improve antineoplastic immune response in patients with MSI-high tumors. For example, programmed cell death protein 1 (PD-1) inhibitors such as Nivolumab, Pembrolizumab, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors like Ipilimumab. Fifth, Neurotrophic tyrosine receptor kinase (NTRK) fusions are targetable genetic mutations that stimulate TKR activity and are detected in <1% of CRC patients. NTRK inhibitors include Larotrectinib and Entrectinib. However, mutations in KRAS, BRAF, and PTN can provide resistance to specific targeted treatments, such as EGFR therapies.
Conclusion: Combination-targeted therapies can overcome resistance mechanisms in novel therapeutic approaches. Future studies can consider detecting molecular mechanisms involved in activating the immune response to tumorigenesis and carcinogenesis progress, such as CRC vaccines and CAR-T cell therapies. Besides, valuable and reliable biomarkers should be identified for screening mCRC patients. Future studies should investigate personalized-targeted therapy for mCRC patients.