Journal article
Src-dependent DBL family members drive resistance to vemurafenib in human melanoma
Cancer research (Chicago, Ill.), Vol.79(19), pp.5074-5087
10/01/2019
DOI: 10.1158/0008-5472.CAN-19-0244
PMCID: PMC6774858
PMID: 31416844
Abstract
The use of selective BRAF inhibitors (BRAFi) has produced remarkable outcomes for patients with advanced cutaneous melanoma harboring a
BRAF
V600E
mutation. Unfortunately, the majority of patients eventually develop drug-resistant disease. We employed a genetic screening approach to identify gain-of-function mechanisms of BRAFi resistance in two independent melanoma cell lines. Our screens identified both known and unappreciated drivers of BRAFi resistance, including multiple members of the DBL family. Mechanistic studies identified a DBL/RAC1/PAK signaling axis capable of driving resistance to both current and next-generation BRAF inhibitors. However, we show that the SRC inhibitor, saracatinib, can block the DBL-driven resistance. Our work highlights the utility of our straightforward genetic screening method in identifying new drug combinations to combat acquired BRAFi resistance.
Details
- Title: Subtitle
- Src-dependent DBL family members drive resistance to vemurafenib in human melanoma
- Creators
- Charlotte R Feddersen - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa Department of Biology, College of Liberal Arts and Sciences, University of Iowa Holden Comprehensive Cancer Center, University of Iowa; Iowa City, IA, 52246 USAJacob L Schillo - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa Department of Biology, College of Liberal Arts and Sciences, University of Iowa Holden Comprehensive Cancer Center, University of Iowa; Iowa City, IA, 52246 USAAfshin Varzavand - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa Department of Biology, College of Liberal Arts and Sciences, University of Iowa Holden Comprehensive Cancer Center, University of Iowa; Iowa City, IA, 52246 USAHayley R Vaughn - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa Department of Biology, College of Liberal Arts and Sciences, University of Iowa Holden Comprehensive Cancer Center, University of Iowa; Iowa City, IA, 52246 USALexy S Wadsworth - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa Department of Biology, College of Liberal Arts and Sciences, University of Iowa Holden Comprehensive Cancer Center, University of Iowa; Iowa City, IA, 52246 USAAndrew P Voigt - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa Department of Biology, College of Liberal Arts and Sciences, University of Iowa Holden Comprehensive Cancer Center, University of Iowa; Iowa City, IA, 52246 USAEliot Y Zhu - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa Department of Biology, College of Liberal Arts and Sciences, University of Iowa Holden Comprehensive Cancer Center, University of Iowa; Iowa City, IA, 52246 USABrooke M Jennings - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa Department of Biology, College of Liberal Arts and Sciences, University of Iowa Holden Comprehensive Cancer Center, University of Iowa; Iowa City, IA, 52246 USASarah A Mullen - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa Department of Biology, College of Liberal Arts and Sciences, University of Iowa Holden Comprehensive Cancer Center, University of Iowa; Iowa City, IA, 52246 USAJeremy Bobera - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa Department of Biology, College of Liberal Arts and Sciences, University of Iowa Holden Comprehensive Cancer Center, University of Iowa; Iowa City, IA, 52246 USAJesse D Riordan - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa Department of Biology, College of Liberal Arts and Sciences, University of Iowa Holden Comprehensive Cancer Center, University of Iowa; Iowa City, IA, 52246 USAChristopher S Stipp - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa Department of Biology, College of Liberal Arts and Sciences, University of Iowa Holden Comprehensive Cancer Center, University of Iowa; Iowa City, IA, 52246 USAAdam J Dupuy - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa Department of Biology, College of Liberal Arts and Sciences, University of Iowa Holden Comprehensive Cancer Center, University of Iowa; Iowa City, IA, 52246 USA
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.79(19), pp.5074-5087
- DOI
- 10.1158/0008-5472.CAN-19-0244
- PMID
- 31416844
- PMCID
- PMC6774858
- NLM abbreviation
- Cancer Res
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Grant note
- DOI: 10.13039/100000002, name: HHS | National Institutes of Health (NIH), award: T32GM008629
- Language
- English
- Date published
- 10/01/2019
- Academic Unit
- Dermatology; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; The University of Iowa Institute for Vision Research; Pathology; Biology
- Record Identifier
- 9984217538702771
Metrics
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