Case study – Protein expression analysis identifies predictive drug-response markers for the MEK inhibitor trametinibOncolines®2024-01-08T15:27:29+01:00
Protein expression analysis identifies predictive drug-response markers for the MEK inhibitor trametinib
Trametinib is a highly selective MEK inhibitor that is currently approved by the FDA for treatment of cancers which harbor a BRAF-V600 mutation.
In cell viability assays on a panel of 102 cancer cell lines (the Oncolines® cell line panel), BRAF-mutant cell lines were responsive to trametinib, while KRAS and NRAS-mutants showed variable responses, reflecting clinical observations (Figure 1).
To identify mutation-independent drug-response biomarkers, we correlated the trametinib IC50 profile in the 102 cancer cell lines to the expression levels of thousands of proteins in the same cell lines using bioinformatics analysis.
The expression of phosphorylated MEK is strongly correlated with increased sensitivity to trametinib (Figure 2), suggesting that increased activation of the MAPK pathway sensitizes cell lines to trametinib.
 Blumenschein et al. (2015) Ann Oncol. 26, 894-901
Figure 1: Waterfall plot and gene mutation analysis showing the ranking of drug response based on IC50 values of 102 cancer cell lines profiled with the MEK inhibitor trametinib.
Figure 2: Protein expression analyses. (left) Top 10 strongest negative correlations between protein expression and 10log IC50 values of trametinib (purple) and in-house Oncolines® reference compounds (blue). A strong correlation is observed between response to trametinib and phosphorylated MEK (Pearson’s r = 0.44). (right) Correlation between response to trametinib and protein expression of phosphorylated MEK. Data points colored purple indicate KRAS-mutant cell lines, whereas blue data points indicate KRAS wild-type cell lines.