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Cancer Res. 2015 Dec 15;75(24):5211-8. doi: 10.1158/0008-5472.CAN-15-0885. Epub 2015 Nov 24.

SBI-0640756 Attenuates the Growth of Clinically Unresponsive Melanomas by Disrupting the eIF4F Translation Initiation Complex.

Author information

1
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
2
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montréal, Canada. Department of Oncology, McGill University, Montréal, Canada.
3
Division of Cancer Epidemiology and Genetics, Laboratory of Translational Genomics, NCI, Bethesda, Maryland.
4
Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, Texas.
5
Cancer and Cell Biology Division, The Translational Genomics Research Institute (TGen), Phoenix, Arizona.
6
Departments of Dermatology and Pathology, Yale University, School of Medicine, New Haven, Connecticut.
7
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. zeev@ronailab.net.

Abstract

Disrupting the eukaryotic translation initiation factor 4F (eIF4F) complex offers an appealing strategy to potentiate the effectiveness of existing cancer therapies and to overcome resistance to drugs such as BRAF inhibitors (BRAFi). Here, we identified and characterized the small molecule SBI-0640756 (SBI-756), a first-in-class inhibitor that targets eIF4G1 and disrupts the eIF4F complex. SBI-756 impaired the eIF4F complex assembly independently of mTOR and attenuated growth of BRAF-resistant and BRAF-independent melanomas. SBI-756 also suppressed AKT and NF-κB signaling, but small-molecule derivatives were identified that only marginally affected these pathways while still inhibiting eIF4F complex formation and melanoma growth, illustrating the potential for further structural and functional manipulation of SBI-756 as a drug lead. In the gene expression signature patterns elicited by SBI-756, DNA damage, and cell-cycle regulatory factors were prominent, with mutations in melanoma cells affecting these pathways conferring drug resistance. SBI-756 inhibited the growth of NRAS, BRAF, and NF1-mutant melanomas in vitro and delayed the onset and reduced the incidence of Nras/Ink4a melanomas in vivo. Furthermore, combining SBI-756 and a BRAFi attenuated the formation of BRAFi-resistant human tumors. Taken together, our findings show how SBI-756 abrogates the growth of BRAF-independent and BRAFi-resistant melanomas, offering a preclinical rationale to evaluate its antitumor effects in other cancers.

PMID:
26603897
PMCID:
PMC4681635
DOI:
10.1158/0008-5472.CAN-15-0885
[Indexed for MEDLINE]
Free PMC Article

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