Profound MEK inhibitor response in a cutaneous melanoma harboring a GOLGA4-RAF1 fusion.
Journal: 2019/March - Journal of Clinical Investigation
ISSN: 1558-8238
Abstract:
BRAF and CRAF are critical components of the MAPK signaling pathway which is activated in many cancer types. In approximately 1% of melanomas, BRAF or CRAF are activated through structural arrangements. We describe here a metastatic melanoma with a GOLGA4-RAF1 fusion and pathogenic variants in CTNNB1 and CDKN2A. Anti-CTLA4/anti-PD1 combination immunotherapy failed to control tumor progression. In the absence of other actionable variants the patient was administered MEK inhibitor therapy on the basis of its potential action against RAF1 fusions. This resulted in a profound and clinically significant response. We demonstrated that GOLGA4-RAF1 expression was associated with ERK activation, elevated expression of the RAS/RAF downstream co-effector ETV5, and a high Ki67 index. These findings provide a rationale for the dramatic response to targeted therapy. This study shows that thorough molecular characterization of treatment-resistant cancers can identify therapeutic targets and personalize management, leading to improved patient outcomes.
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J Clin Invest 129(5): 1940-1945

Profound MEK inhibitor response in a cutaneous melanoma harboring a <em>GOLGA4-RAF1</em> fusion

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Department of Pathology, and
Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia.
Clinical Pathology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia.
Department of Medical Oncology and
Department of Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia.
Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia.
Department of Surgery, St Vincent’s Hospital, Fitzroy, Australia.
Clinical School, Austin Health, Heidelberg, Australia.
Department of Surgery, Royal Melbourne Hospital, Parkville, Australia.
Corresponding author.
Christopher R. McEvoy: gro.camretep@yovecm.rehpotsirhc; Huiling Xu: gro.camretep@ux.gniliuh; Kortnye Smith: gro.camretep@htims.eyntrok; Dariush Etemadmoghadam: moc.liamg@dameted; Huei San Leong: gro.camretep@gnoeL.naSieuH; David Y. Choong: gro.camretep@gnoohc.divad; David J. Byrne: gro.camretep@enryb.divad; Amir Iravani: gro.camretep@inavarI.rimA; Sophie Beck: gro.camretep@kceb.eihpos; Linda Mileshkin: gro.camretep@nikhselim.adnil; Richard W. Tothill: ua.ude.bleminu@llihtotr; David D. Bowtell: gro.camretep@lletwob.divad; Bindi M. Bates: gro.camretep@setab.idnib; Violeta Nastevski: gro.camretep@iksvetsaN.ykciV; Judy Browning: gro.camretep@gninworB.yduJ; Anthony H. Bell: gro.camretep@lleb.ynohtna; Chloe Khoo: moc.liamtoh@oohk.eolhc; Jayesh Desai: ua.gro.hm@iaseD.hseyaJ; Andrew P. Fellowes: gro.camretep@sewollef.werdna; Stephen B. Fox: gro.camretep@xoF.nehpetS; Owen W.J. Prall: gro.camretep@llarp.newo
Address correspondence to: Christopher R. McEvoy, Department of Pathology, Peter MacCallum Cancer Centre, 305 Gratton Street, Melbourne, Victoria 3000, Australia. Phone: 61.3.85598442; Email: gro.camretep@yovecm.rehpotsirhC.
Authorship note: CRM and HX contributed equally to this work.
Christopher R. McEvoy: gro.camretep@yovecm.rehpotsirhc; Huiling Xu: gro.camretep@ux.gniliuh; Kortnye Smith: gro.camretep@htims.eyntrok; Dariush Etemadmoghadam: moc.liamg@dameted; Huei San Leong: gro.camretep@gnoeL.naSieuH; David Y. Choong: gro.camretep@gnoohc.divad; David J. Byrne: gro.camretep@enryb.divad; Amir Iravani: gro.camretep@inavarI.rimA; Sophie Beck: gro.camretep@kceb.eihpos; Linda Mileshkin: gro.camretep@nikhselim.adnil; Richard W. Tothill: ua.ude.bleminu@llihtotr; David D. Bowtell: gro.camretep@lletwob.divad; Bindi M. Bates: gro.camretep@setab.idnib; Violeta Nastevski: gro.camretep@iksvetsaN.ykciV; Judy Browning: gro.camretep@gninworB.yduJ; Anthony H. Bell: gro.camretep@lleb.ynohtna; Chloe Khoo: moc.liamtoh@oohk.eolhc; Jayesh Desai: ua.gro.hm@iaseD.hseyaJ; Andrew P. Fellowes: gro.camretep@sewollef.werdna; Stephen B. Fox: gro.camretep@xoF.nehpetS; Owen W.J. Prall: gro.camretep@llarp.newoAddress correspondence to: Christopher R. McEvoy, Department of Pathology, Peter MacCallum Cancer Centre, 305 Gratton Street, Melbourne, Victoria 3000, Australia. Phone: 61.3.85598442; Email: gro.camretep@yovecm.rehpotsirhC.Authorship note: CRM and HX contributed equally to this work.
Received 2018 Aug 14; Accepted 2019 Feb 26.

Abstract

The serine/threonine kinases BRAF and CRAF are critical components of the MAPK signaling pathway that is activated in many cancer types. In approximately 1% of melanomas, BRAF or CRAF is activated through structural arrangements. We describe a metastatic melanoma with a GOLGA4-RAF1 fusion and pathogenic variants in catenin β 1 (CTNNB1) and cyclin-dependent kinase inhibitor 2A (CDKN2A). Anti–cytotoxic T-lymphocyte–associated protein 4/anti–programmed cell death 1 (anti-CTLA4/anti–PD-1) combination immunotherapy failed to control tumor progression. In the absence of other actionable variants, the patient was administered MEK inhibitor therapy on the basis of its potential action against RAF1 fusions. This resulted in a profound and clinically significant response. We demonstrated that GOLGA4-RAF1 expression was associated with ERK activation, elevated expression of the RAS/RAF downstream coeffector ETV5, and a high Ki67 index. These findings provide a rationale for the dramatic response to targeted therapy. This study shows that molecular characterization of treatment-resistant cancers can identify therapeutic targets and personalize therapy management, leading to improved patient outcomes.

Keywords: Genetics, Oncology
Keywords: Cancer, Melanoma, Molecular pathology
Abstract

Acknowledgments

We thank Melbourne Genomic Health Alliances (MGHA) and the Australian Genomic Health Alliance (NHMRC grant 1113531) for funding the I-PREDICT study. We also thank the following individuals at the Peter MacCallum Cancer Centre: Richard Lupat for assistance with GRIDSS (Genome Rearrangement IDentification Software Suite) analysis; Jason Li for setting up the analysis pipeline for the nCounter data set; Jenna Stewart and David Yoannidis for technical assistance; Kelly Waldek for advice on IHC; Chung-Yan Ma for discussions on immunomarkers; and Michael McKay and Glen Gurra for critical discussions of the manuscript.

Acknowledgments

Funding Statement

No specific Grant number available

Funding Statement

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Footnotes

Conflict of interest: The authors have declared that no conflict of interest exists.

Copyright: © 2019, The American Society for Clinical Investigation.

Reference information: J Clin Invest. 2019;129(5):1940–1945.https://doi.org/10.1172/JCI123089.

Footnotes

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