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

• Main Authors: Antonia Strippoli, Alessandra Cocomazzi, Michele Basso, Tonia Cenci, Riccardo Ricci, Francesco Pierconti, Alessandra Cassano, Vincenzo Fiorentino, Carlo Barone, Emilio Bria, Lucia Ricci-Vitiani, Giampaolo Tortora, Luigi Maria Larocca, Maurizio Martini
• Format: Article
• Language: English
• Published: MDPI AG 2020-03-01
• Series: Cancers
• Subjects: c-myc; colorectal cancer; egfr inhibitor resistance; targeted therapy
• Online Access: https://www.mdpi.com/2072-6694/12/3/638

Alterations in the transcriptional factor c-MYC could be involved in the anti-EGFR resistance in metastatic colorectal cancer (mCRC). The c-MYC expression was evaluated in 121 RAS and BRAF wild-type mCRC before treatment with anti-EGFR+Folfiri therapy and in 33 subsequent metastases collected during target therapy (TT) or in TT resistance phase. We analyzed the expression and the functional role of some c-MYC linked miRNAs (miR-31-3p, miR-143 and miR-145) in our patient group and in two CRC cell lines, also performing a c-MYC target PCR array. Patients with higher c-MYC expression (HME) showed a significant lower PFS and OS when compared to those with low c-MYC expression (LME). HME pattern was significantly more frequent in the metastases after TT and significantly associated to anti-EGFR molecular resistance alterations. We also found a significant correlation between the expression of the above-mentioned c-MYC linked miRNAs, c-MYC level and anti-EGFR resistance. Moreover, expression gene profiling pointed out the pivotal role of c-MYC in CRC-related cell-cycle, apoptosis, signal transduction and cell-growth pathways. c-MYC expression might distinguish patients with a lower PFS and OS in anti-EGFR treated mCRC. The individuation of some miRNAs involved in the c-MYC pathway regulation and the downstream c-MYC effector genes could provide a new possible target to overcome the anti-EGFR resistance in mCRC.