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Personalized oncology and BRAFK601N melanoma: model development, drug discovery, and clinical correlation

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Mutations in BRAF are the most prominent activating mutations in melanoma and are increasingly recognized in other cancers. There is currently no accepted treatment regimen for patients with mutant BRAFK601N melanoma, and the study of melanoma driven by BRAF mutations at the 601 locus is lacking due to a paucity of cellular model systems. Therefore, we sought to better understand the treatment and clinical approach to patients with mutant BRAFK601N melanoma and subsequently develop a novel personalized oncology platform for rare or treatment-refractory cancers.

Methods

We developed and characterized the first patient-derived, naturally occurring BRAFK601N melanoma model, described herein as OHRI-MEL-13, and assessed efficacy using the Prestwick Chemical Library and select targeted therapeutics.

Results

OHRI-MEL-13 exhibits loss of heterozygosity of BRAF, closely mimics the original tumor’s gene expression profile, is tumorigenic in immune-deficient murine models, and is available for public accession through American Type Culture Collection. We present in silico modeling data, which illustrates the therapeutic failure of BRAFV600E-targeted therapies in BRAFK601N mutants. Our platform elucidated a unique role for MEK inhibition with cobimetinib, which resulted in short-term clinical success by reducing the metastatic burden.

Conclusion

Our model of BRAFK601N-activated melanoma was developed, thoroughly characterized, and made available for public accession. This model served to demonstrate the feasibility of a novel personalized oncology platform that could be optimized at an institutional level for rare variant or treatment-refractory cancers. We also demonstrate the clinical utility of monotherapy MEK inhibition in a case of BRAFK601N melanoma.

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Availability of data and materials

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

Code availability

Not applicable.

Abbreviations

ATCC:

American Type Culture Collection

CNS:

Central nervous system

DNA:

Deoxyribonucleic acid

FDA:

U.S. Food & Drug Administration

FFPE:

Formalin-fixed, paraffin-embedded

MAPK:

Mitogen-activated protein kinase

MD:

Molecular dynamics

NCI:

National Cancer Institute

RNA:

Ribonucleic acid

RPMI:

Roswell Park Memorial Institute

WT:

Wild type

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Acknowledgements

We acknowledge technical assistance from those in the clinical histology and molecular genetics laboratories of the Ottawa Hospital. We also acknowledge the resourcefulness of Dr. Jim Dimitroulakos for managing the appropriate ethics protocols to obtain and utilize patient-derived specimens. Most importantly, we acknowledge the donation of tissue from all patients who contribute to our work, present and ongoing.

Funding

The work performed herein was partially funded by a Terry Fox Research Institute, New Frontiers Program in Cancer grant number TFF-122868 and by a Canadian Institutes in Health Research Foundation Scheme grant number FDN-148428. BAK was funded by a Vanier Canada Graduate Scholarship. OV was supported by a CIHR Master’s Award. AB was funded by an NSERC postdoctoral fellowship. MEW was supported by an Ontario Graduate Scholarship.

Author information

Authors and Affiliations

  1. Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, K1H 8L6, Canada

    Brian A. Keller, Brian J. Laight, Oliver Varette, Marie-Ève Wedge, Benjamin McSweeney, Catia Cemeus, Julia Petryk, Bryan Lo, Carolyn Nessim, Michael Ong, Harold L. Atkins, Jean-Simon Diallo, Carolina S. Ilkow & John C. Bell

  2. Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, K1H 8M5, Canada

    Brian A. Keller, Oliver Varette, Harold L. Atkins, Jean-Simon Diallo, Carolina S. Ilkow & John C. Bell

  3. Department of Pathology and Laboratory Medicine, The Ottawa Hospital, 501 Smyth Road, Ottawa, K1H 8L6, Canada

    Brian A. Keller, Bryan Lo & Bruce Burns

  4. Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie-Curie Private, Ottawa, K1N 6N5, Canada

    Aron Broom & Roberto A. Chica

  5. Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, K1H 8M5, Canada

    Marie-Ève Wedge

  6. Molecular Oncology Diagnostics Laboratory, The Ottawa Hospital, 501 Smyth Road, Ottawa, K1H 8L6, Canada

    Bryan Lo

  7. Division of General Surgery, The Ottawa Hospital, 501 Smyth Road, Ottawa, K1H 8L6, Canada

    Carolyn Nessim

  8. Division of Medical Oncology, The Ottawa Hospital, 501 Smyth Road, Ottawa, K1H 8L6, Canada

    Michael Ong

  9. The Ottawa Hospital Blood and Marrow Transplant Program, The Ottawa Hospital, 501 Smyth Road, Ottawa, K1H 8L6, Canada

    Harold L. Atkins

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  1. Brian A. Keller
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  2. Brian J. Laight
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  3. Oliver Varette
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  4. Aron Broom
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  5. Marie-Ève Wedge
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  6. Benjamin McSweeney
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  7. Catia Cemeus
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  8. Julia Petryk
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  9. Bryan Lo
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  10. Bruce Burns
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  11. Carolyn Nessim
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  12. Michael Ong
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  13. Roberto A. Chica
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  14. Harold L. Atkins
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  15. Jean-Simon Diallo
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  16. Carolina S. Ilkow
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  17. John C. Bell
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Contributions

BAK obtained specimen, created cell line, designed experiments, conducted some experiments, analyzed data, and wrote manuscript. BJL performed BRAF and MEK cytotoxicity studies. BJL and OV performed high-throughput drug screening and associated data analysis. AB and RAC performed enhanced sampling molecular dynamics studies and associated modeling. MEW, BM, CC, and JP assisted in technical capacities and helped execute selected experiments. BJL conducted and analyzed transcriptome analyses. BB performed histological analysis of both patient-derived and mouse specimens. CN performed surgeries. MO provided medical oncology care for patient and assessed medical progress. HLA, J-SD, CSI and JCB supervised all aspects of project and participated in manuscript writing. All authors were involved in manuscript editing.

Corresponding author

Correspondence to Brian A. Keller.

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Conflict of interest

The authors declare no competing interests. OHRI-MEL-13 was licensed to the American Type Culture Collection (ATCC) by the Ottawa Hospital Research Institute according to the terms set forth in the ATCC Material Deposit Agreement.

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Experiments including mouse models were undertaken at the University of Ottawa Animal Care and Veterinary Services facility and approved by the local institutional ethics board.

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Full informed consent from the patient participant was obtained and approved according to the Ottawa Health Science Network Research Ethics Board protocol number 20120559-01.

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Consent for publication has been obtained according to the Ottawa Health Science Network Research Ethics Board protocol outlined above.

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Keller, B.A., Laight, B.J., Varette, O. et al. Personalized oncology and BRAFK601N melanoma: model development, drug discovery, and clinical correlation. J Cancer Res Clin Oncol 147, 1365–1378 (2021). https://doi.org/10.1007/s00432-021-03545-2

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