title: SBI-0640756 Attenuates the Growth of Clinically Unresponsive Melanomas by Disrupting the eIF4F Translation Initiation Complex.
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.
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Pinkerton
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montréal, Canada. Department of Oncology, McGill University, Montréal, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Hulea
authors.affiliation: Division of Cancer Epidemiology and Genetics, Laboratory of Translational Genomics, NCI, Bethesda, Maryland.
authors.forename: Tongwu
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Stefan
authors.initials: S
authors.lastname: Grotegut
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Yann
authors.initials: Y
authors.lastname: Cheli
authors.affiliation: Cancer and Cell Biology Division, The Translational Genomics Research Institute (TGen), Phoenix, Arizona.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yin
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Eric
authors.initials: E
authors.lastname: Lau
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Hyungsoo
authors.initials: H
authors.lastname: Kim
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Surya K
authors.initials: SK
authors.lastname: De
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Elisa
authors.initials: E
authors.lastname: Barile
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.affiliation: Departments of Dermatology and Pathology, Yale University, School of Medicine, New Haven, Connecticut.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bosenberg
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Jian-Liang
authors.initials: JL
authors.lastname: Li
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Brian
authors.initials: B
authors.lastname: James
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hassig
authors.affiliation: Division of Cancer Epidemiology and Genetics, Laboratory of Translational Genomics, NCI, Bethesda, Maryland.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brown
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montréal, Canada. Department of Oncology, McGill University, Montréal, Canada.
authors.forename: Ivan
authors.initials: I
authors.lastname: Topisirovic
authors.affiliation: Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. zeev@ronailab.net.
authors.forename: Ze'ev A
authors.initials: ZA
authors.lastname: Ronai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006801:Humans; D007769:Lactams / Q000494:pharmacology*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D015363:Quinolones / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D039562:Eukaryotic Initiation Factor-4F; D007769:Lactams; D015363:Quinolones; C000607014:SBI-0640756