JUN dependency in distinct early and late BRAF inhibition adaptation states of melanoma

Bjoern Titz; Anastasia Lomova; Allison Le; Willy Hugo; Xiangju Kong; Johanna Ten Hoeve; Michael Friedman; Hubing Shi; Gatien Moriceau; Chunying Song; Aayoung Hong; Mohammad Atefi; Richard Li; Evangelia Komisopoulou; Antoni Ribas; Roger S Lo; Thomas G Graeber

doi:10.1038/celldisc.2016.28

JUN dependency in distinct early and late BRAF inhibition adaptation states of melanoma

Cell Discov. 2016 Sep 6:2:16028. doi: 10.1038/celldisc.2016.28. eCollection 2016.

Authors

Bjoern Titz¹, Anastasia Lomova¹, Allison Le¹, Willy Hugo², Xiangju Kong², Johanna Ten Hoeve¹, Michael Friedman¹, Hubing Shi², Gatien Moriceau², Chunying Song², Aayoung Hong², Mohammad Atefi³, Richard Li¹, Evangelia Komisopoulou¹, Antoni Ribas⁴, Roger S Lo⁵, Thomas G Graeber⁶

Affiliations

¹ 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.
² Division of Dermatology, Department of Medicine, University of California Los Angeles , Los Angeles, CA, USA.
³ Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles , Los Angeles, CA, USA.
⁴ 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.
⁵ 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.
⁶ 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.

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.

Keywords: BRAF inhibition; Drug resistance; EMT; melanoma; phospho-proteomics.

Abstract

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