Monosomy 3 Is Linked to Resistance to MEK Inhibitors in Uveal Melanoma

Svenja Mergener,Jens T Siveke,Samuel Peña-Llopis

doi:10.3390/ijms22136727

Abstract

The use of MEK inhibitors in the therapy of uveal melanoma (UM) has been investigated widely but has failed to show benefits in clinical trials due to fast acquisition of resistance. In this study, we investigated a variety of therapeutic compounds in primary-derived uveal melanoma cell lines and found monosomy of chromosome 3 (M3) and mutations in BAP1 to be associated with higher resistance to MEK inhibition. However, reconstitution of BAP1 in a BAP1-deficient UM cell line was unable to restore sensitivity to MEK inhibition. We then compared UM tumors from The Cancer Genome Atlas (TCGA) with mutations in BAP1 with tumors with wild-type BAP1. Principal component analysis (PCA) clearly differentiated both groups of tumors, which displayed disparate overall and progression-free survival data. Further analysis provided insight into differential expression of genes involved in signaling pathways, suggesting that the downregulation of the eukaryotic translation initiation factor 2A (EIF2A) observed in UM tumors with BAP1 mutations and M3 UM cell lines might lead to a decrease in ribosome biogenesis while inducing an adaptive response to stress. Taken together, our study links loss of chromosome 3 with decreased sensitivity to MEK inhibition and gives insight into possible related mechanisms, whose understanding is fundamental to overcome resistance in this aggressive tumor.

Highlights

Uveal melanoma (UM) is the most common malignancy of the eye, affecting 5 to 7 million people per year [1]
We evaluated the sensitivity of three disomy 3 (D3) (92-1, UPMD1 and UPMD2) and three monosomy of chromosome 3 (M3) (UPMM2, UPMM3 and UPMM4) UM cell lines to a variety of chemotherapeutic and molecularly targeted compounds at nine different concentrations to obtain comprehensive dose-response curves throughout different inhibitor classes
In order to find potential new therapeutic approaches for the treatment of UM, we evaluated the response of six UM cell lines to a variety of chemotherapeutic and targeted compounds

Summary

Introduction

Uveal melanoma (UM) is the most common malignancy of the eye, affecting 5 to 7 million people per year [1]. Targeted therapy has been proven beneficial in cancers with certain molecular changes resulting in a dependency on specific signaling pathways. This has been shown by successful treatment of endothelial growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with EGFR inhibitors, treatment of breast cancer gene (BRCA)-mutated ovarian cancer with poly-ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors and treatment of BRAF-mutated cutaneous melanoma and NSCLC with BRAF inhibitors or MEK inhibitors [8,9,10,11]. In uveal melanoma, an extraordinarily low mutational burden complicates the identification of suitable targets [12]

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Results

Conclusion