Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):13679-13684. doi: 10.1073/pnas.1712064115. Epub 2017 Dec 11.

Single-cell analysis resolves the cell state transition and signaling dynamics associated with melanoma drug-induced resistance.

Author information

1
NanoSystems Biology Cancer Center, California Institute of Technology, Pasadena, CA 91125.
2
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125.
3
NanoSystems Biology Cancer Center, California Institute of Technology, Pasadena, CA 91125; weiwei@mednet.ucla.edu aribas@mednet.ucla.edu heath@caltech.edu.
4
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095.
5
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095.
6
Department of Medicine, University of California, Los Angeles, CA 90095.
7
Division of Translational Oncology, Carlos III Health Institute, 28029 Madrid, Spain.
8
Department of Surgery, Division of Surgical-Oncology, University of California, Los Angeles, CA 90095.
9
Crump Institute for Molecular Imaging, University of California, Los Angeles, CA 90095.
10
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; weiwei@mednet.ucla.edu aribas@mednet.ucla.edu heath@caltech.edu.

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.

KEYWORDS:

Markov chain model; adaptive resistance; cell state transition; melanoma; single-cell analysis

PMID:
29229836
PMCID:
PMC5748184
DOI:
10.1073/pnas.1712064115
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center