Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 52, Pages 13679-13684Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1712064115
Keywords
single-cell analysis; cell state transition; adaptive resistance; Markov chain model; melanoma
Categories
Funding
- NIH [U54 CA199090, P01 CA168585, R35 CA197633, T32-CA009120]
- Dr. Robert Vigen Memorial Fund
- Garcia-Corsini Family Fund
- Ressler Family Fund
- Grimaldi Family Fund
- Jean Perkins Foundation
- University of California, Los Angeles, Broad Stem Cell Research Center Seed Fund for Small Cell Cancer Pilot Studies
- Phelps Family Foundation
- ACS Research Scholar Award [RSG-12-257-01-TBE]
- MRA Established Investigator Award [20120279]
- University of California, Los Angeles, Clinical and Translational Science Institute Grant [UL1TR000124]
- University of California, Los Angeles, Jonsson Comprehensive Cancer Center (JCCC) membership [NIH/NCI P30CA016042]
- V Foundation-Gil Nickel Family Endowed Fellowship
- SEOM
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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 BRAF(V600)-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. Markovmodeling 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.
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