title: JUN dependency in distinct early and late BRAF inhibition adaptation states of melanoma.
abstract: A prominent mechanism of acquired resistance to BRAF inhibitors in BRAF (V600) -mutant melanoma is associated with the upregulation of receptor tyrosine kinases. Evidences suggested that this resistance mechanism is part of a more complex cellular adaptation process. Using an integrative strategy, we found this mechanism to invoke extensive transcriptomic, (phospho-) proteomic and phenotypic alterations that accompany a cellular transition to a de-differentiated, mesenchymal and invasive state. Even short-term BRAF-inhibitor exposure leads to an early adaptive, differentiation state change-characterized by a slow-cycling, persistent state. The early persistent state is distinct from the late proliferative, resistant state. However, both differentiation states share common signaling alterations including JUN upregulation. Motivated by the similarities, we found that co-targeting of BRAF and JUN is synergistic in killing fully resistant cells; and when used up-front, co-targeting substantially impairs the formation of the persistent subpopulation. We confirmed that JUN upregulation is a common response to BRAF inhibitor treatment in clinically treated patient tumors. Our findings demonstrate that events shared between early- and late-adaptation states provide candidate up-front co-treatment targets.
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Titz
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Anastasia
authors.identifier: 0000-0003-4713-2089
authors.initials: A
authors.lastname: Lomova
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Le
authors.affiliation: Division of Dermatology, Department of Medicine, University of California Los Angeles , Los Angeles, CA, USA.
authors.forename: Willy
authors.identifier: 0000-0002-1426-7190
authors.initials: W
authors.lastname: Hugo
authors.affiliation: Division of Dermatology, Department of Medicine, University of California Los Angeles , Los Angeles, CA, USA.
authors.forename: Xiangju
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ten Hoeve
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Friedman
authors.affiliation: Division of Dermatology, Department of Medicine, University of California Los Angeles , Los Angeles, CA, USA.
authors.forename: Hubing
authors.initials: H
authors.lastname: Shi
authors.affiliation: Division of Dermatology, Department of Medicine, University of California Los Angeles , Los Angeles, CA, USA.
authors.forename: Gatien
authors.initials: G
authors.lastname: Moriceau
authors.affiliation: Division of Dermatology, Department of Medicine, University of California Los Angeles , Los Angeles, CA, USA.
authors.forename: Chunying
authors.initials: C
authors.lastname: Song
authors.affiliation: Division of Dermatology, Department of Medicine, University of California Los Angeles , Los Angeles, CA, USA.
authors.forename: Aayoung
authors.initials: A
authors.lastname: Hong
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles , Los Angeles, CA, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Atefi
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Komisopoulou
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Division of Surgical-Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Division of Dermatology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Lo
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA; California NanoSystems Institute, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Thomas G
authors.identifier: 0000-0001-8574-9181
authors.initials: TG
authors.lastname: Graeber
keywords: BRAF inhibition; Drug resistance; EMT; melanoma; phospho-proteomics