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ResearchIn-Press PreviewDermatologyOncology Open Access | 10.1172/JCI185220

Combinatorial therapy regimens targeting preclinical models of melanoma resistant to immune checkpoint blockade

Imran Khan,1 Aida Rodriguez-Brotons,1 Anukana Bhattacharjee,2 Vladimir Bezrookove,1 Altaf Dar,1 David De Semir,1 Mehdi Nosrati,1 Ryan Ice,1 Liliana Soroceanu,1 Stanley P. Leong,1 Kevin B. Kim,1 Yihui Shi,1 James E. Cleaver,3 James R. Miller,1 Pierre-Yves Desprez,1 John M. Kirkwood,4 Marcus Bosenberg,5 Nathan Salomonis,2 Sean McAllister,1 and Mohammed Kashani-Sabet1

1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

Find articles by Khan, I. in: PubMed | Google Scholar

1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

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1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

Find articles by Bhattacharjee, A. in: PubMed | Google Scholar

1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

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1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

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1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

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1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

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1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

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1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

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1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

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1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

Find articles by Kim, K. in: PubMed | Google Scholar

1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

Find articles by Shi, Y. in: PubMed | Google Scholar

1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

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1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

Find articles by Miller, J. in: PubMed | Google Scholar

1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

Find articles by Desprez, P. in: PubMed | Google Scholar

1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

Find articles by Kirkwood, J. in: PubMed | Google Scholar |

1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

Find articles by Bosenberg, M. in: PubMed | Google Scholar

1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

Find articles by Salomonis, N. in: PubMed | Google Scholar |

1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

Find articles by McAllister, S. in: PubMed | Google Scholar

1California Pacific Medical Center (CPMC) Research Institute, San Francisco, United States of America

2Division of Biomedical Informatics, Cincinnati Children’ s Hospital Medical Center, Cincinnati, United States of America

3Department of Dermatology, University of California San Francisco, San Francisco, United States of America

4Melanoma Program, Division of Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, United States of America

5Department of Dermatology, Yale University, New Haven, United States of America

Find articles by Kashani-Sabet, M. in: PubMed | Google Scholar

Published July 10, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI185220.
Copyright © 2025, Khan et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 10, 2025 - Version history
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Abstract

Few effective therapeutic options exist following progression on immune checkpoint blockade (ICB) for melanoma. Here we utilize a platform incorporating transcriptomic profiling, high-throughput drug screening (HTDS) and murine models to demonstrate the pre-clinical efficacy of several combinatorial regimens against ICB-resistant melanoma. Transcriptomic analysis of ICB-resistant melanomas demonstrated activation of several targetable pathways. HTDS targeting these pathways identified several effective combinations in ICB-resistant patient-derived xenograft models. The combination of cobimetinib and regorafenib (termed Cobi+Reg) emerged as a particularly promising regimen, with efficacy against distinct molecular melanoma subtypes and following progression on ICB in immunocompetent models. Transcriptomic and spatial analysis of Cobi+Reg-treated tumors demonstrated upregulation of antigen presentation machinery, with concomitantly increased activated T cell infiltration. Combining Cobi+Reg with ICB was superior to either modality in vivo. This analytical platform exploits the biology of ICB-resistant melanoma to identify therapeutic vulnerabilities, resulting in the identification of drug combinations that form the basis for rational clinical trial design in the setting of advanced melanoma resistant to ICB.

Graphical Abstract
graphical abstract
Supplemental material

View Original western and blot images from Figure 1G

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Version history
  • Version 1 (July 10, 2025): In-Press Preview
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