SPRED1 deletion confers resistance to MAPK inhibition in melanoma

Ablain, Julien; Liu, Sixue; Moriceau, Gatien; Lo, Roger S.; Zon, Leonard I.

doi:10.1084/jem.20201097

SPRED1 deletion confers resistance to MAPK inhibition in melanoma

Julien Ablain

0000-0002-4509-3568

Julien Ablain

Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing

Stem Cell Program and Division of Hematology/Oncology, Boston Children’s Hospital and Dana Farber Cancer Institute, Boston, MA

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Sixue Liu

0000-0003-0323-4104

Sixue Liu

Data curation, Formal analysis, Visualization, Writing - review & editing

Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA

David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA

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Gatien Moriceau

0000-0003-3904-7669

Gatien Moriceau

Methodology, Validation

Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA

David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA

Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA

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Roger S. Lo

0000-0002-5337-5004

Roger S. Lo

Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing - review & editing

Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA

David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA

Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA

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Leonard I. Zon

0000-0003-0860-926X

Leonard I. Zon

Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Visualization, Writing - original draft, Writing - review & editing

Stem Cell Program and Division of Hematology/Oncology, Boston Children’s Hospital and Dana Farber Cancer Institute, Boston, MA

Harvard Stem Cell Institute, Harvard University, Cambridge, MA

Howard Hughes Medical Institute, Boston, MA

Correspondence to Leonard I. Zon: zon@enders.tch.harvard.edu

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Julien Ablain

https://orcid.org/0000-0002-4509-3568

Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing

Stem Cell Program and Division of Hematology/Oncology, Boston Children’s Hospital and Dana Farber Cancer Institute, Boston, MA

Sixue Liu

https://orcid.org/0000-0003-0323-4104

Data curation, Formal analysis, Visualization, Writing - review & editing

Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA

David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA

Gatien Moriceau

https://orcid.org/0000-0003-3904-7669

Methodology, Validation

Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA

David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA

Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA

Roger S. Lo

https://orcid.org/0000-0002-5337-5004

Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing - review & editing

Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA

Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA

David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA

Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA

Leonard I. Zon

https://orcid.org/0000-0003-0860-926X

Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Visualization, Writing - original draft, Writing - review & editing

Stem Cell Program and Division of Hematology/Oncology, Boston Children’s Hospital and Dana Farber Cancer Institute, Boston, MA

Harvard Stem Cell Institute, Harvard University, Cambridge, MA

Howard Hughes Medical Institute, Boston, MA

Correspondence to Leonard I. Zon: zon@enders.tch.harvard.edu

Disclosures: R.S. Lo reported grants from Pfizer, Merck, OncoSec, and BMS outside the submitted work. L.I. Zon reported personal fees from Scholar Rock Inc., Fate Therapeutics, CAMP4 Therapeutics, Amagma Therapeutics, Celularity, and Cellarity outside the submitted work. No other disclosures were reported.

Received: May 28 2020

Revision Received: October 12 2020

Accepted: November 06 2020

Online Issn: 1540-9538

Print Issn: 0022-1007

Funding:

Howard Hughes Medical Institute (NO AWARD)

Jonsson Comprehensive Cancer Center (NO AWARD)

Melanoma Research Alliance (NO AWARD)

National Cancer Institute (R01CA103846, P01CA163222, K99CA201465, 1R01CA176111A1, 1R21CA215910-011, P01CA244118)

V Foundation for Cancer Research (NO AWARD)

2020

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

J Exp Med (2021) 218 (3): e20201097.

https://doi.org/10.1084/jem.20201097

Functional evaluation of genetic lesions can discover a role in cancer initiation and progression and help develop novel therapeutic strategies. We previously identified the negative MAPK regulator SPRED1 as a novel tumor suppressor in KIT-driven melanoma. Here, we show that SPRED1 is also frequently deleted in human melanoma driven by mutant BRAF. We found that SPRED1 inactivation in human melanoma cell lines and primary zebrafish melanoma conferred resistance to BRAF^V600E inhibition in vitro and in vivo. Mechanistically, SPRED1 loss promoted melanoma cell proliferation under mutant BRAF inhibition by reactivating MAPK activity. Consistently, biallelic deletion of SPRED1 was observed in a patient whose melanoma acquired resistance to MAPK-targeted therapy. These studies combining work in human cells and in vivo modeling in zebrafish demonstrate a new mechanism of resistance to BRAF^V600E inhibition in melanoma.

2020

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