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Updated: Feb 17, 2026
A Melanoma Patient-Derived Xenograft Model
Published on: May 20, 2019
Single-cell analysis resolves the cell state transition and signaling dynamics associated with melanoma drug-induced
Yapeng Su1,2, Wei Wei3,4,5, Lidia Robert6
1NanoSystems Biology Cancer Center, California Institute of Technology, Pasadena, CA 91125.
Abstract:
Continuous BRAF inhibition of BRAF mutant melanomas triggers a series of cell state changes that lead to therapy resistance and escape from immune control before establishing acquired resistance genetically. We used genome-wide transcriptomics and single-cell phenotyping to explore the response kinetics to BRAF inhibition for a panel of patient-derived BRAFV600 -mutant melanoma cell lines. A subset of plastic cell lines, which followed a trajectory covering multiple known cell state transitions, provided models for more detailed biophysical investigations. Markov modeling revealed that the cell state transitions were reversible and mediated by both Lamarckian induction and nongenetic Darwinian selection of drug-tolerant states. Single-cell functional proteomics revealed activation of certain signaling networks shortly after BRAF inhibition, and before the appearance of drug-resistant phenotypes. Drug targeting those networks, in combination with BRAF inhibition, halted the adaptive transition and led to prolonged growth inhibition in multiple patient-derived cell lines.
Insights
Targeting BRAF in melanoma causes adaptive cell changes leading to resistance. Combining BRAF inhibitors with network-targeting drugs can overcome this resistance by halting adaptive transitions.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- BRAF inhibitors are standard treatment for BRAF-mutant melanomas.
- Tumors often develop resistance to BRAF inhibitors through complex adaptive mechanisms.
- Understanding these adaptive changes is crucial for improving therapeutic strategies.
Purpose of the Study:
- To investigate the cell state dynamics and resistance mechanisms in BRAF-mutant melanoma under continuous BRAF inhibition.
- To identify signaling networks activated early during the adaptive response.
- To evaluate combination therapies targeting BRAF and identified networks.
Main Methods:
- Genome-wide transcriptomics and single-cell phenotyping of patient-derived melanoma cell lines.
- Markov modeling to analyze cell state transitions.
- Single-cell functional proteomics to assess signaling network activation.
- In vitro drug combination studies.
Main Results:
- Continuous BRAF inhibition induced reversible cell state transitions, characterized by Lamarckian and Darwinian mechanisms.
- Specific signaling networks were activated early, preceding the development of drug-resistant phenotypes.
- Combination therapy (BRAF inhibitor + network-targeting drug) effectively halted adaptive transitions.
- This combination strategy led to prolonged growth inhibition in multiple cell lines.
Conclusions:
- Melanoma cells undergo adaptive transitions upon BRAF inhibition, contributing to therapy resistance.
- Early-activated signaling networks are critical mediators of this adaptive response.
- Targeting these networks concurrently with BRAF inhibition offers a promising strategy to overcome resistance and improve treatment outcomes.
