Editors' ChoiceCancer

Targeting an “undruggable” protein

+ See all authors and affiliations

Sci. Signal.  08 Aug 2017:
Vol. 10, Issue 491, eaao5809
DOI: 10.1126/scisignal.aao5809

Blocking an interaction with the RNA-binding protein NEFLE or the kinase CAMKIIγ might provide new ways of inhibiting c-Myc in cancers.

Through its role in regulating the expression of various genes associated with cell proliferation and survival, the transcription factor c-Myc is implicated in promoting the growth and progression of various cancers. However, it is currently challenging to target c-Myc directly, thus clinicians must find other avenues of inhibiting its activity in patients. Some hepatocellular carcinomas (HCC) have amplifications in the gene expressing c-Myc. Dang et al. found through bioinformatics that many RNA-binding proteins (RBPs) are also dysregulated in HCC and that this is associated with poor prognosis in patients. The gene encoding one of these RBPs, negative elongation factor E (NELFE), was coamplified in many c-MYC–associated HCCs. NEFLE preferentially facilitated the binding of c-Myc to target promoters, as well as increasing the transcript stability of several c-Myc–regulated genes, thereby supporting the tumor transcriptome. NEFLE expression enhanced c-Myc–driven development of HCC in mice. Thus, the development of peptides that interfere with the NELFE-MYC interaction may be an effective therapy in HCC patients. Unlike many other types of cancers, T cell lymphomas (TCLs) have an increased abundance of the c-Myc protein without rearrangements or amplification at the genetic level. Gu et al. found that the kinase CAMKIIγ phosphorylated and stabilized c-Myc. CAMKIIγ abundance positively correlated with that of c-Myc in patient TCL samples, and inhibiting CAMKIIγ reduced TCL burden in mice and had minimal off-target toxicity, suggesting that CAMKIIγ inhibitors might be a therapeutic option for TCL patients. Together, these studies present new opportunities for targeting an “undruggable” protein.

Highlighted Articles

View Abstract

Navigate This Article