Homo sapiens Transcriptome or Gene expression. Homo sapiens

Small molecule mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors are used to treat metastatic cutaneous melanoma and are being considered for treatment of other types of cancers. Ocular side effects termed MEK associated retinopathy (MEKAR) have been observed in up to 80% of patients treated with MEK inhibitors and are thought to be caused by toxicity to the retinal pigment epithelium (RPE). To determine why MEK inhibitors cause MEKAR, we treated induced pluripotent stem cell derived RPE (iPSC-RPE) with MEK inhibitors and performed RNASeq to identify differentially expressed genes. In addition to genes involved in the MEK pathway we found a number of other genes whose expression was significantly up or down-regulated. Early Growth Response 1 (EGR1), a gene encoding a zinc finger transcription factor, was the gene most affected and was down-regulated by MEK inhibitors in three melanoma cell lines. While the viability of the melanoma lines was compromised by MEK inhibitors, iPSC-RPE viability was unaffected. Similarly, knock-down of EGR1 impaired the viability of melanoma cells but not iPSC-RPE cells. When treated with mithramycin A, an inhibitor of EGR1 activity that does not affect the MEK pathway, melanoma cell viability was significantly impaired but iPSC-RPE remained viable. As no MEKAR-like symptoms have been reported in cancer patients treated with mithramycin A, we suggest that MEKAR results from inhibition of the MEK pathway exclusive of EGR1. These findings suggest that therapeutically targeting EGR1 or genes downstream of EGR1 may offer the anti-oncogenic effects of MEK inhibitors without adverse ocular side effects.