c-MYC Expression Is a Possible Keystone in the Colorectal Cancer Resistance to EGFR Inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Anti-epidermal growth factor receptor (anti-EGFR) therapy is a standard treatment for metastatic colorectal cancer (mCRC).
• Resistance to anti-EGFR therapy remains a significant clinical challenge, necessitating identification of predictive biomarkers and therapeutic targets.
• The transcriptional factor c-MYC is implicated in various cancers and may play a role in anti-EGFR resistance.

Purpose of the Study:

• To investigate the role of c-MYC expression in anti-EGFR resistance in patients with RAS and BRAF wild-type mCRC.
• To analyze the correlation between c-MYC, its related microRNAs (miRNAs), and treatment outcomes.
• To identify potential therapeutic targets for overcoming anti-EGFR resistance.

Main Methods:

• c-MYC expression was assessed in 121 mCRC patients before anti-EGFR therapy and in 33 metastases during or after treatment.
• Expression of c-MYC-linked miRNAs (miR-31-3p, miR-143, miR-145) was analyzed.
• Functional roles were studied in CRC cell lines, alongside a c-MYC target PCR array and gene expression profiling.

Main Results:

• Higher c-MYC expression (HME) was significantly associated with shorter progression-free survival (PFS) and overall survival (OS).
• HME was more frequent in post-treatment metastases and linked to molecular alterations causing anti-EGFR resistance.
• A significant correlation was found between c-MYC, related miRNAs, and anti-EGFR resistance, highlighting c-MYC's role in cell-cycle and growth pathways.

Conclusions:

• c-MYC expression serves as a potential biomarker for predicting poor outcomes in mCRC patients treated with anti-EGFR therapy.
• Identifying miRNAs and downstream effectors in the c-MYC pathway offers novel strategies to overcome anti-EGFR resistance.
• Targeting the c-MYC pathway could represent a promising approach to improve treatment efficacy in mCRC.