EGFR signaling defines Mcl⁻1 survival dependency in neuroblastoma

Cancer Biology & Therapy
Srilatha NalluriK C Goldsmith

Abstract

The pediatric solid tumor neuroblastoma (NB) often depends on the anti-apoptotic protein, Mcl(-)1, for survival through Mcl(-)1 sequestration of pro-apoptotic Bim. High affinity Mcl(-)1 inhibitors currently do not exist such that novel methods to inhibit Mcl(-)1 clinically are in high demand. Receptor tyrosine kinases (RTK) regulate Mcl(-)1 in many cancers and play a role in NB survival, yet how they regulate Bcl(-)2 family interactions in NB is unknown. We found that NB cell lines derived to resist the Bcl(-)2/-xl/-w antagonist, ABT-737, acquire a dependence on Mcl(-)1 and show increased expression and activation of the RTK, EGFR. Mcl(-)1 dependent NB cell lines derived at diagnosis and from the same tumor following relapse also have increased EGFR expression compared to those dependent on Bcl(-)2. Inhibition of EGFR by shRNA or erlotinib in Mcl(-)1 dependent NBs disrupts Bim binding to Mcl(-)1 and enhances its affinity for Bcl(-)2, restoring sensitivity to ABT-737 as well as cytotoxics in vitro. Mechanistically treatment of NBs with small molecule inhibitors of EGFR (erlotinib, cetuximab) and ERK (U0126) increases Noxa expression and dephosphorylates Bim to promote Bim binding to Bcl(-)2. Thus, EGFR regulates Mcl(-)1 dependen...Continue Reading

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Citations

May 19, 2018·The FEBS Journal·Jason E Conage-Pough, Lawrence H Boise
Apr 12, 2020·Journal of Experimental & Clinical Cancer Research : CR·Xinyou YuMing Li
Sep 2, 2018·Molecular and Cellular Pediatrics·Stefan E G BurdachKlaus-Michael Debatin
Jun 6, 2021·Molecular Cancer Therapeutics·Krista M DaltonAnthony C Faber

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Methods Mentioned

BETA
xenografts
co-immunoprecipitation
Co-IP
pull down
co-IPs
genotyping
PCR
Gel Filtration

Software Mentioned

Biosystems
Prism
Applied
SeqScape

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