Please confirm you are human (Sign Up for free to never see this)
← Back to Search
Systematic Analysis Of BRAFV600E Melanomas Reveals A Role For JNK/c-Jun Pathway In Adaptive Resistance To Drug-induced Apoptosis
M. Fallahi-Sichani, N. Moerke, M. Niepel, T. Zhang, N. Gray, P. Sorger
Published 2015 · Biology, Medicine
Save to my Library
Download PDFAnalyze on Scholarcy
Drugs that inhibit RAF/MEK signaling, such as vemurafenib, elicit profound but often temporary anti‐tumor responses in patients with BRAFV600E melanoma. Adaptive responses to RAF/MEK inhibition occur on a timescale of hours to days, involve homeostatic responses that reactivate MAP kinase signaling and compensatory mitogenic pathways, and attenuate the anti‐tumor effects of RAF/MEK inhibitors. We profile adaptive responses across a panel of melanoma cell lines using multiplex biochemical measurement, single‐cell assays, and statistical modeling and show that adaptation involves at least six signaling cascades that act to reduce drug potency (IC50) and maximal effect (i.e., Emax ≪ 1). Among these cascades, we identify a role for JNK/c‐Jun signaling in vemurafenib adaptation and show that RAF and JNK inhibitors synergize in cell killing. This arises because JNK inhibition prevents a subset of cells in a cycling population from becoming quiescent upon vemurafenib treatment, thereby reducing drug Emax. Our findings demonstrate the breadth and diversity of adaptive responses to RAF/MEK inhibition and a means to identify which steps in a signaling cascade are most predictive of phenotypic response.
This paper references
Dynamic Proteomics of Individual Cancer Cells in Response to a Drug
A. Cohen (2008)
Phosphorylation and Functional Inactivation of TSC2 by Erk Implications for Tuberous Sclerosisand Cancer Pathogenesis
L. Ma (2005)
Towards a unified model of RAF inhibitor resistance.
D. Solit (2014)
Lysate Microarrays Enable High-throughput, Quantitative Investigations of Cellular Signaling*
M. Sevecka (2011)
JNK supports survival in melanoma cells by controlling cell cycle arrest and apoptosis
Vasileia-Ismini Alexaki (2008)
TORC 1 suppression predicts responsiveness to RAF and MEK inhibition in BRAFmutant melanoma
RB Corcoran (2013)
Metrics other than potency reveal systematic variation in responses to cancer drugs.
M. Fallahi-Sichani (2013)
Profiling phospho-signaling networks in breast cancer using reverse-phase protein arrays
T. S. Gujral (2013)
Dynamic Reprogramming of the Kinome in Response to Targeted MEK Inhibition in Triple-Negative Breast Cancer
J. Duncan (2012)
Rewired ERK-JNK signaling pathways in melanoma.
Pablo Lopez-Bergami (2007)
Activation of Jun/AP-1 by protein kinase A.
R. D. de Groot (1992)
Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation
T. Eberlein (2012)
Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy.
H. Shi (2014)
Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis
S. Spencer (2009)
Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma
G. Bollag (2010)
Bayesian Network Approach to Cell Signaling Pathway Modeling
K. Sachs (2002)
c-Jun promotes cellular survival by suppression of PTEN
K. Hettinger (2007)
Phenformin enhances the therapeutic benefit of BRAFV600E inhibition in melanoma
P. Yuan (2013)
mTOR Signaling in Growth Control and Disease
M. Laplante (2012)
Melanoma whole exome sequencing identifies V600EB-RAF amplification-mediated acquired B-RAF inhibitor resistance
H. Shi (2012)
Targeting c-Jun and JunB proteins as potential anticancer cell therapy
E. N. Gurzov (2008)
Data-driven modelling of signal-transduction networks
Kevin A. Janes (2006)
Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.
K. Flaherty (2012)
BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling
H. Vin (2013)
Mutations of the BRAF gene in human cancer
Helen Davies (2002)
Causal Protein-Signaling Networks Derived from Multiparameter Single-Cell Data
K. Sachs (2005)
The role of mitogen‐ and stress‐activated protein kinase pathways in melanoma
P. Lopez-Bergami (2011)
Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation
R. Nazarian (2010)
Variability and memory of protein levels in human cells
A. Sigal (2006)
Role of JNK activation in apoptosis: A double-edged sword
J. Liu (2005)
Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K.
Jessie Villanueva (2010)
Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma
Chong Sun (2014)
Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas.
Piro Lito (2012)
TORC1 Suppression Predicts Responsiveness to RAF and MEK Inhibition in BRAF-Mutant Melanoma
R. Corcoran (2013)
c-Jun Regulates Phosphoinositide-dependent Kinase 1 Transcription
Pablo Lopez-Bergami (2009)
Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells.
T. Muranen (2012)
Multicomponent therapeutics for networked systems
C. Keith (2005)
Phosphoproteomic analysis of basal and therapy‐induced adaptive signaling networks in BRAF and NRAS mutant melanoma
I. Fedorenko (2015)
Treatment of BRAF‐Mutant Melanoma: The Role of Vemurafenib and Other Therapies
S. Jang (2014)
Role of JNK activation in apoptosis： A double-edged sword
Partial least-squares regression: a tutorial
P. Geladi (1986)
Negative feedback and adaptive resistance to the targeted therapy of cancer.
S. Chandarlapaty (2012)
COT/MAP3K8 drives resistance to RAF inhibition through MAP kinase pathway reactivation
C. Johannessen (2010)
The Cancer Cell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity
J. Barretina (2012)
Variability and Robustness in T Cell Activation from Regulated Heterogeneity in Protein Levels
O. Feinerman (2008)
A Compendium of Signals and Responses Triggered by Prodeath and Prosurvival Cytokines*S
Suzanne Gaudet (2005)
Comparing signaling networks between normal and transformed hepatocytes using discrete logical models.
J. Sáez-Rodríguez (2011)
AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity.
S. Chandarlapaty (2011)
The MAPK pathway in melanoma
L. Fecher (2008)
The Ki‐67 protein: From the known and the unknown
T. Scholzen (2000)
Training Signaling Pathway Maps to Biochemical Data with Constrained Fuzzy Logic: Quantitative Analysis of Liver Cell Responses to Inflammatory Stimuli
M. Morris (2011)
Tumor adaptation and resistance to RAF inhibitors
Piro Lito (2013)
A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition.
H. Shi (2014)
Single-Cell Mass Cytometry of Differential Immune and Drug Responses Across a Human Hematopoietic Continuum
S. Bendall (2011)
Discovery of potent and selective covalent inhibitors of JNK.
T. Zhang (2012)
Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer.
B. Carver (2011)
Exponentially weighted moving principal components analysis and projections to latent structures
S. Wold (1994)
Systematic identification of genomic markers of drug sensitivity in cancer cells
M. Garnett (2012)
License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited
p38α suppresses normal and cancer cell proliferation by antagonizing the JNK–c-Jun pathway
L. Hui (2007)
Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib.
J. Sosman (2012)
Cytokine-Induced Signaling Networks Prioritize Dynamic Range over Signal Strength
Kevin A. Janes (2008)
Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks.
B. Magnuson (2012)
Exploring the Contextual Sensitivity of Factors that Determine Cell-to-Cell Variability in Receptor-Mediated Apoptosis
S. Gaudet (2012)
Highly multiplexed single-cell analysis of formalin-fixed, paraffin-embedded cancer tissue
M. Gerdes (2013)
The retinoblastoma protein is phosphorylated during specific phases of the cell cycle
K. Buchkovich (1989)
Activator Protein-1 Mediates Induced but not Basal Epidermal Growth Factor Receptor Gene Expression
A. Johnson (2000)
Causal proteinsignaling networks derived from multiparameter single-cell data
K Sachs (2005)
Cells surviving fractional killing by TRAIL exhibit transient but sustainable resistance and inflammatory phenotypes
D. Flusberg (2013)
c‐Jun regulates cell cycle progression and apoptosis by distinct mechanisms
R. Wisdom (1999)
Profiling phosphosignaling networks in breast cancer using reversephase protein arrays
TS Gujral (2013)
The LKB1 tumor suppressor negatively regulates mTOR signaling.
R. Shaw (2004)
Identification of the MEK1(F129L) activating mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-RafV600E mutation.
H. Wang (2011)
Rb binds c‐Jun and activates transcription
M. Nead (1998)
Inhibition of mutated, activated BRAF in metastatic melanoma.
K. Flaherty (2010)
Differential Determinants of Cancer Cell Insensitivity to Antimitotic Drugs Discriminated by a One-Step Cell Imaging Assay
Yangzhong Tang (2013)
Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase.
Philippe P Roux (2004)
MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition.
N. Wagle (2014)
mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt.
Kathryn E. O'Reilly (2006)
RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)
P. Poulikakos (2011)
Comparing signaling networks between normal and a 2015 The Authors
J Saez-Rodriguez (2011)
Abstract 5400: Antiangiogenic gene therapy with VB111 is active in glioblastoma xenografts
Andrew Brenner (2011)
RRID:AB_614942) and goat anti-rabbit IgG conjugated to DyLight 800 (Thermo Pierce Cat# 35571, RRID:AB_614947)
CDK-Mediated Regulation of Cell Functions via c-Jun Phosphorylation and AP-1 Activation
Tony J Vanden Bush (2011)
This paper is referenced by
A biomaterial screening approach reveals microenvironmental mechanisms of drug resistance.
A. Schwartz (2017)
Euxanthone Impairs the Metastatic Potential of Osteosarcoma by Reducing COX‐2 Expression
X. Chen (2018)
Inflammatory but not mitogenic contexts prime synovial fibroblasts for compensatory signaling responses to p38 inhibition
D. S. Jones (2018)
Phosphoprotein patterns predict trametinib responsiveness and optimal trametinib sensitisation strategies in melanoma
Jan Rožanc (2018)
Robust latent-variable interpretation of in vivo regression models by nested resampling
A. Caulk (2019)
HDAC8 Regulates a Stress Response Pathway in Melanoma to Mediate Escape from BRAF Inhibitor Therapy.
M. Emmons (2019)
Dissecting Pathway Disturbances Using Network Topology and Multi-platform Genomics Data
Yuping Zhang (2018)
Sporadic ERK pulses drive non-genetic resistance in drug-adapted BRAFV600E melanoma cells
L. Gerosa (2019)
Recursive model for dose-time responses in pharmacological studies
Saugato Rahman Dhruba (2019)
Other Positions and Employment
M. Niepel (2015)
Leveraging transcriptional dynamics to improve BRAF inhibitor responses in melanoma
Inna Smalley (2019)
The transcription cofactor c-JUN mediates phenotype switching and BRAF inhibitor resistance in melanoma
R. Ramsdale (2015)
Cytotoxic Activities and Molecular Mechanisms of the Beauvericin and Beauvericin G1 Microbial Products against Melanoma Cells
Haet Nim Lim (2020)
Highly multiplexed imaging of single cells using a high-throughput cyclic immunofluorescence method
Jia-Ren Lin (2015)
MALT1 promotes melanoma progression through JNK/c-Jun signaling
Y. Wang (2017)
A Biomaterial Screening Approach to Reveal Microenvironmental Mechanisms of Drug Resistance
A. Schwartz (2017)
EGFR inhibition triggers an adaptive response by co-opting antiviral signaling pathways in lung cancer.
Ke Gong (2020)
Integrating Genomics Into Clinical Pediatric Oncology Using the Molecular Tumor Board at the Memorial Sloan Kettering Cancer Center
Michael V. Ortiz (2016)
An investigation of proteomic data for application in precision medicine
Kevin Matlock (2018)
Beyond static biomarkers—The dynamic response potential of signaling networks as an alternate biomarker?
Jaeyeon Kim (2015)
Stroma-induced phenotypic plasticity offers phenotype-specific targeting to improve melanoma treatment.
Kotryna Seip (2018)
JNKs function as CDK4-activating kinases by phosphorylating CDK4 and p21
B. Colleoni (2017)
JNK Pathway Activation Modulates Acquired Resistance to EGFR/HER2-Targeted Therapies.
Simin Manole (2016)
Epigenetic Mechanisms of Escape from BRAF Oncogene Dependency
Mehwish Khaliq (2019)
Epigenetic modulation extends the oncogene addiction paradigm on the basis of tumor cell differentiation state
Mehwish Khaliq (2020)
The JNK Signaling Pathway in Inflammatory Skin Disorders and Cancer †
Manel B. Hammouda (2020)
Common and cell-type specific responses to anti-cancer drugs revealed by high throughput transcript profiling
M. Niepel (2017)
Trajectories from Snapshots: Integrated proteomic and metabolic single-cell assays reveal multiple independent adaptive responses to drug tolerance in a BRAF-mutant melanoma cell line
Yapeng Su (2019)
The cancer cell proteome and transcriptome predicts sensitivity to targeted and cytotoxic drugs
M. Rydenfelt (2019)
JUN-Mediated Downregulation of EGFR Signaling Is Associated with Resistance to Gefitinib in EGFR-mutant NSCLC Cell Lines
Kian Kani (2017)
Multi-omic single-cell snapshots reveal multiple independent trajectories to drug tolerance in a melanoma cell line
Yapeng Su (2020)
A Methodology For Parametrizing Discrete Model of Biological Networks
Nathan Renaudie (2018)See more