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ETS-targeted therapy: can it substitute for MEK inhibitors?



The RAS/MAPK pathway has been intensively studied in cancer. Constitutive activation of ERK1 and ERK2 is frequently found in cancer cells from a variety of tissues. In clinical practice and clinical trials, small molecules targeting receptor tyrosine kinases or components in the MAPK cascade are used for treatment. MEK1 and MEK2 are ideal targets because these enzymes are physiologically important and have narrow substrate specificities and distinctive structural characteristics. Despite success in pre-clinical testing, only two MEK inhibitors, trametinib and cobimetinib, have been approved, both for treatment of BRAF-mutant melanoma. Surprisingly, the efficacy of MEK inhibitors in other tumors has been disappointing. These facts suggest the need for a different approach. We here consider transcription factor ETS1 and ETS2 as alternate therapeutic targets because they are major MAPK downstream effectors.

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The lack of clinical efficacy of MEK inhibitors is attributed mostly to a subsequent loss of negative feedback regulation in the MAPK pathway. To overcome this obstacle, second-generation MEK inhibitors, so-called "feedback busters," have been developed. However, their efficacy is still unsatisfactory in the majority of cancers. To substitute ETS-targeted therapy, therapeutic strategies to modulate the transcription factor in cancer must be considered. Chemical targeting of ETS1 for proteolysis is a promising strategy; Src and USP9X inhibitors might achieve this by accelerating ETS1 protein turnover. Targeting the ETS1 interface might have great therapeutic value because ETS1 dimerizes itself or with other transcription factors to regulate target genes. In addition, transcriptional cofactors, including CBP/p300 and BRD4, represent intriguing targets for both ETS1 and ETS2.


ETS-targeted therapy appears to be promising. However, it may have a potential problem. It might inhibit autoregulatory negative feedback loops in the MAPK pathway, with consequent resistance to cell death by ERK1 and ERK2 activation. Further research is warranted to explore clinically applicable ways to inhibit ETS1 and ETS2.

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