Project Explorer

Systematic analysis of BRAFV600E melanomas reveals a role for JNK/c-Jun pathway in adaptive resistance to drug-induced apoptosis

Mohammad Fallahi-Sichani1, Nathan J. Moerke1, Mario Niepel1, Tinghu Zhang2,3, Nathanael S. Gray2,3, and Peter K. Sorger1

1 HMS LINCS Center, Harvard Medical School, Boston, MA; 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA; 3 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA

Mol Syst Biol (2015) 11: 797
doi:10.15252/msb.20145877 / PMID:25814555 / PMCID:PMC4380931

Overview

In the paper referenced above, we systematically analyzed adaptive responses to RAF/MEK inhibitors across a panel of BRAFV600E melanoma lines and revealed a role for the JNK/c-Jun pathway and cell-to-cell variability in adaptive drug resistance. The 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.

Using the exploration tools and downloadable data below, we invite you to explore the data and computational approaches presented in this paper. Please cite this work when using any of the data or analyses presented here.

PLSR loadings browser

Explore the findings of our partial least squares regression (PLSR) model through this interactive data browser. Shown across all 10 cell lines are the PLSR loadings for the first two model components (PC1 and PC2) representing relative contribution to the model of each of the 21 molecular signals analyzed over time relative to cell viability.

VIP scores browser

Explore the variable importance in the projection (VIP) score of each model variable relative to cell viability across all time points studied. This data browser also allows you to visualize the relative importance of each variable in the context of the molecular pathways impinging upon drug-induced adaptive responses in these cell lines.

Available Data and Signatures

Data Viability and apoptosis in BRAF(V600E/D) melanoma cell lines monitored by imaging (HMS Dataset #20217) Details Download (.xlsx)
Data Phosphorylation state and protein levels measured in BRAF(V600E/D) melanoma cell lines monitored by Reverse Phase Protein Arrays (RPPA)(HMS Dataset #20218) Details Download (.xlsx)
Data Phosphorylation state and protein levels measured in BRAF(V600E/D) melanoma cell lines monitored by imaging (HMS Dataset #20219) Details Download (.xlsx)
Signature PLSR model loadings (pMEK and pERK included) from analysis of the covariation of molecular signals with cell viability and apoptosis fraction in BRAF(V600E/D) melanoma cell lines (HMS Dataset #20229) Details Download (.xlsx)
Signature PLSR model loadings (pMEK and pERK excluded) from analysis of the covariation of molecular signals with cell viability and apoptosis fraction in BRAF(V600E/D) melanoma cell lines (HMS Dataset #20230) Details Download (.xlsx)
Signature Average variable importance in the projection (VIP) scores from the PLSR models analyzing the covariation of molecular signals with cell viability and apoptosis fraction in BRAF(V600E/D) melanoma cell lines (HMS Dataset #20231) Details Download (.xlsx)
Software A link to our HMS LINCS GitHub for access to the code for the data visualization tools presented on this project explorer website. hmslincs at GitHub