Intravital Imaging Reveals How BRAF Inhibition Generates Drug-Tolerant Microenvironments with High Integrin β1/FAK Signaling
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Intravital imaging of BRAF-mutant melanoma cells containing an ERK/MAPK biosensor reveals how the tumor microenvironment affects response to BRAF inhibition by PLX4720. Initially, melanoma cells respond to PLX4720, but rapid reactivation of ERK/MAPK is observed in areas of high stromal density. This is linked to "paradoxical" activation of melanoma-associated fibroblasts by PLX4720 and the promotion of matrix production and remodeling leading to elevated integrin β1/FAK/Src signaling in melanoma cells. Fibronectin-rich matrices with 3-12 kPa elastic modulus are sufficient to provide PLX4720 tolerance. Co-inhibition of BRAF and FAK abolished ERK reactivation and led to more effective control of BRAF-mutant melanoma. We propose that paradoxically activated MAFs provide a "safe haven" for melanoma cells to tolerate BRAF inhibition.
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These changes can aid development of therapy resistance and contribute to undesirable side effects.
“These changes can aid the development of therapy resistance78–80 and contribute to undesirable side effects80.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [78]
The Significance and Discussion sections say that BRAF inhibition alters the tumor stroma, helping melanoma cells tolerate treatment and potentially sustaining the pool from which resistant clones emerge. The source does not support the side-effects portion of the claim; its Results section instead reports no adverse effects, such as weight loss, in mice receiving the tested drug combination. (LLM, conf=0.87)
Experimental — accuracy not yet measuredBRAF inhibitors can activate stromal fibroblasts and thereby promote a compensatory mechanism for activating ERK-MAPK in cancer cells.
“BRAF inhibitors can activate stromal fibroblasts and thereby promote a compensatory mechanism for activating ERK–MAPK in cancer cells78.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [78]
The tumor microenvironment is a complex ecosystem comprised of multiple cell types that support the growth of tumor cells, facilitate tumor progression, and modulate therapeutic response to anti-cancer treatments.
“The tumor microenvironment is a complex ecosystem comprised of multiple cell types that support the growth of tumor cells, facilitate tumor progression, and modulate therapeutic response to anti-cancer treatments [29,99,100,120,121].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [100]
The increase in extracellular matrix stiffness activated integrin, FAK, and Src signaling in melanoma cells that ultimately enabled them to become drug tolerant by adaptive reactivation of MAPK signaling.
“The increase in extracellular matrix stiffness activated integrin, FAK, and Src signaling in melanoma cells that ultimately enabled them to become drug tolerant by adaptive reactivation of MAPK signaling [100].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [100]
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- Authors
- Hirata, E., Girotti, M. R., Viros, A., Hooper, S., Spencer-Dene, B., Matsuda, M., Larkin, J., Marais, R., & Sahai, E.
- Affiliations
- Cancer Research UK (GB)
- Kyoto University (JP)
- Royal Marsden NHS Foundation Trust (GB)
- Cancer Research UK Manchester Institute (GB)
- Corresponding author
- Sahai, Erik
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 27
- Issue
- 4
- Pages
- 574-588
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4402404
- OpenAlex
- W1973767497
- Cited by
- 593
- References
- 49
- Citations by year
- 2026: 38 · 2025: 33 · 2024: 42 · 2023: 47 · 2022: 51 · 2021: 64 · 2020: 63 · 2019: 66 · 2018: 53 · 2017: 59 · 2016: 62 · 2015: 15
- FWCI
- 27.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by-nc-nd)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- Wellcome Trust (100282, 100282/Z/12/Z)
- Francis Crick Institute (10009, 10144)
- NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
- Cancer Research UK (15154, 17240, 19279)
- Japan Society for the Promotion of Science (15H05949)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- BRAF inhibition, melanoma, drug tolerance, tumor microenvironment, beta1 integrin, focal adhesion kinase, Src signaling, PLX4720, fibronectin matrix, extracellular matrix stiffness, intravital imaging, combination therapy
- MeSH terms
- Animals, Humans, Indoles, Melanoma, Mice, Inbred C57BL, Sulfonamides, Signal Transduction, Drug Resistance, Neoplasm, Integrin beta1, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Mice, Focal Adhesion Protein-Tyrosine Kinases, Tumor Microenvironment
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