Dasatinib resensitizes BRAF/MEK inhibitor efficacy in patient-derived xenografts from patients with progression on BRAF/MEK inhibitor treatment
Although BRAF/MEK inhibitor (BRAFi/MEKi) therapy initially shows high efficacy in patients with <i>BRAF</i> <sup>V600 E/K</sup> cutaneous melanoma, resistance develops in over 75% of cases. We tested robustness of the umbrella trial strategy in this population by analyzing relationships between genomic status of a gene and associated downstream consequences at the protein level. The results revealed weak relationships among mutations, copy-number amplification, and protein expression and activation. An <i>in vivo</i> compound repurposing screen using 11 clinically relevant agents from an NCI-portfolio with pan-RTK, non-RTK, and/or PI3K-mTOR specificity identified dasatinib as most capable of restoring sensitivity to BRAFi/MEKi in patient-derived xenograft (PDX) models originating from tumors that had progressed on BRAFi ± MEKi. High baseline expression of BRAFi/MEKi resistance-associated proteins (e.g., AXL, YAP, HSP70, and phospho-AKT) was predictive of the response to BRAFi/MEKi + dasatinib combination therapy. These findings suggest that adding dasatinib may help overcome resistance and restore anti-tumor activity in patients with BRAFi/MEKi-refractory cutaneous melanoma.
Authors
- Marie E. Portuallo (ORCID: https://orcid.org/0000-0001-8019-0032)
- Tetiana Godok
- Dylan Fingerman (ORCID: https://orcid.org/0000-0001-7343-8482)
- Hongkai Ji (ORCID: https://orcid.org/0000-0002-6480-0141)
- Kasey L. Couts (ORCID: https://orcid.org/0000-0002-2088-2229)
- Gregory Schuyler Brown (ORCID: https://orcid.org/0000-0002-9619-4094)
- Govind Warrier (ORCID: https://orcid.org/0000-0002-6625-448X)
- Mitchell E. Fane (ORCID: https://orcid.org/0000-0001-6163-5753)
- Jeremy Bravo
- Yogesh Goyal (ORCID: https://orcid.org/0000-0003-3502-6465)
- Meihan Wei (ORCID: https://orcid.org/0009-0009-5631-8855)
- Vissy M. Elad
- Eneda Toska (ORCID: https://orcid.org/0000-0002-8974-9792)
- Yeqing Chen (ORCID: https://orcid.org/0000-0002-5602-3311)
- Y.N. Vashisht Gopal (ORCID: https://orcid.org/0000-0002-3118-0011)
- Jessie Villanueva (ORCID: https://orcid.org/0000-0001-5701-2609)
- Keerthana M. Arun
- Jianyi Ding
- Andrew Kossenkov
- Xiangfan Yin
- Vito W. Rebecca
- Gretchen M. Alicea
- Meenhard Herlyn
- Min Xiao
- Katherine Nathanson
- Michael A. Davies
- Qin Liu
Institutions
- The Wistar Institute (US)
- Northwestern University (US)
- Bloomberg (United States) (US)
- The University of Texas MD Anderson Cancer Center (US)
- Johns Hopkins University (US)
- Johns Hopkins Medicine (US)
- Sidney Kimmel Comprehensive Cancer Center (US)
- University of Colorado Anschutz Medical Campus (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- iScience
- Published
- 2026-01-13
- DOI
- https://doi.org/10.1016/j.isci.2026.114669
- Primary Topic
- Melanoma and MAPK Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Melanoma Research Alliance
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- AIM at Melanoma
- National Institutes of Health
- University of Texas MD Anderson Cancer Center
- National Cancer Institute