Oncotarget

Interview with Dr. Chesler from the Institute of Cancer Research and the Royal Marsden NHS Trust

Oncotarget published " Inhibition of mTOR-kinase destabilizes MYCN and is a potential therapy for MYCN-dependent tumors " which reported that In childhood cancer, aberrant expression of MYC and MYCN genes delineates a group of aggressive tumours responsible for a major proportion of pediatric cancer deaths.

These authors designed a chemical-genetic screen that identifies compounds capable of enhancing proteasomal elimination of MYCN oncoprotein.

The authors isolated several classes of compound that selectively kill MYCN expressing cells and we focus on inhibitors of PI3K/mTOR pathway in this study.

Mechanistically, the ability of these compounds to degrade MYCN requires complete blockade of mTOR but not PI3 kinase activity and we highlight NVP-BEZ235 as a PI3K/mTOR inhibitor with an ideal activity profile.

These data establish that MYCN expression is a marker indicative of likely clinical sensitivity to mTOR inhibition, and provide a rationale for the selection of clinical candidate MYCN-destabilizers likely to be useful for the treatment of MYCN-driven cancers.

Dr. Louis Chesler from The Institute of Cancer Research and The Royal Marsden NHS Trust said, "Aberrant expression of the transcription factors MYC and MYCN (a MYC homologue with expression limited to undifferentiated neurons) delivers a potent oncogenic stimulus in cancer, making MYC oncoproteins attractive targets for pharmacologic inhibition. "

Aberrant expression of the transcription factors MYC and MYCN delivers a potent oncogenic stimulus in cancer, making MYC oncoproteins attractive targets for pharmacologic inhibition.

Pharmacologic inhibition of MYCN oncoprotein is therefore of great interest in pediatric cancer; however, direct targeting of MYC, or MYC oncoproteins in general, has not yet delivered viable therapeutics to the clinic.

Genetic screens utilizing RNA-interference have identified relationships between expression of MYC and a defined set of additional genes, suppression of which induces lethality restricted to cells with MYC or MYCN expression .

Previous work established that in cancer cell lines, excess PI3K pathway signaling modulates the AKT-regulated targets GSK3 βand mTOR, extending the half-life of MYC and outlining a potential pharmacologic approach for targeting MYC stability .

Potent compounds that have mechanistic activity in cells expressing wild-type, but not CPD mutated, MYCN protein should antagonize oncogenic stabilization of MYCN protein and target synthetic lethal relationships associated with MYCN expression.

The Chesler Research Team concluded in their Oncotarge Research Output that advances in medicinal chemistry have delivered potent small-molecules to clinical use that have the ability to achieve effective in vivo blockade of major oncogenic signaling pathways through either direct targeting of oncoproteins or through synthetic lethal relationships exposed by oncogene expression.

The availability of multiple clinical inhibitors that target pathways of high relevance to cancer treatment mandates thorough mechanistic prioritization.

Here they show that within the class of available inhibitors of PI3K/mTOR pathway, compounds that selectively block mTORC1/mTORC2, such as the combined PI3K/mTOR inhibitor NVP-BEZ235, efficiently target MYCN protein stability and cause in vivo regression of neuroblastoma, a MYCN-driven pediatric tumor.

This has important implications for planned trials of these compounds in pediatric cancer, since multiple PI3K, mTOR and dually targeted PI3K/mTOR drugs are already in active clinical evaluation.

The success of pediatric trials utilizing these agents will depend as much on careful selection of the appropriate agent as on the target patient population likely to benefit from treatment.

DOI - https://doi.org/10.18632/oncotarget.10544

Full text - https://www.oncotarget.com/article/10544/text/

Correspondence to - Louis Chesler - louis.chesler@icr.ac.uk

Keywords - neuroblastoma, mTOR, MYC, MYCN, PI3-kinase

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