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

Antonia Strippoli,Lucia Ricci-Vitiani,Francesco Pierconti,Tonia Cenci,Carlo Barone,Luigi Maria Larocca,Emilio Bria,Maurizio Martini,Giampaolo Tortora,Alessandra Cocomazzi,Michele Basso,Vincenzo Fiorentino,Riccardo Ricci,Alessandra Cassano

doi:10.3390/cancers12030638

Abstract

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.

Highlights

The treatment of metastatic colorectal cancer was deeply changed by the introduction of anti-EGFR “targeted therapy” (TT) [1,2]
When we correlate the expression of c-MYC with the progression free survival time (PFS) and overall survival (OS), we found that patients with higher c-MYC expression (HME) had a significant lower Progression-free survival (PFS) and Overall survival (OS) than those with reduced c-MYC expression
Analyzing the expression of c-MYC in a small subgroup (10 cases) of metastases before the treatment we found that three had HME and seven low c-MYC expression (LME) pattern, showing the same c-MYC expression observed in the corresponding primary tumors

Summary

Introduction

The treatment of metastatic colorectal cancer (mCRC) was deeply changed by the introduction of anti-EGFR “targeted therapy” (TT) [1,2]. Recent reports have demonstrated that divergent kinase signaling pathways frequently converge on common and relatively small downstream effectors [10,11] These molecules, including transcription factors, could represent a “fragile-point” in the kinases-addicted carcinoma and in the “kinome reprogramming phenomena” observed in TT resistance [12]. Several scientific works have described the functional effector role of c-MYC downstream of many other oncogenic kinases such as BRAF and EGFR, probably representing the main fulcrum of the primary and secondary resistance in targeted therapy [14]. In this scenario, several studies have recently demonstrated that some miRNAs (miRs), short noncoding

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