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Comprehensive predictive biomarker analysis for MEK inhibitor GSK1120212
Junping Jing1, Joel Greshock, Joanna Dawn Holbrook
1Cancer Research, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
Molecular Cancer Therapeutics
|December 16, 2011
Summary
GSK1120212, a MEK1/2 inhibitor, shows promise in various cancers. Biomarker analysis identified RAF/RAS mutations, DUSP6 expression, and triple-negative breast cancer as key indicators of sensitivity.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- GSK1120212 is a MEK1 and MEK2 inhibitor in clinical development.
- Identifying predictive biomarkers is crucial for optimizing targeted cancer therapies.
Purpose of the Study:
- To profile sensitivity to GSK1120212 across a wide range of solid and hematologic cancer cell lines.
- To identify predictive biomarkers for GSK1120212 efficacy.
Main Methods:
- Sensitivity profiling of 218 solid tumor and 81 hematologic malignancy cell lines.
- Analysis of mutations (RAF/RAS, PIK3CA/PTEN), gene expression (epithelial-to-mesenchymal transition), and specific gene expression (DUSP6).
Main Results:
- RAF/RAS mutations predicted sensitivity in solid tumors.
- Co-occurring PIK3CA/PTEN mutations led to cytostatic rather than cytotoxic responses in colon cancer.
- DUSP6 expression correlated with sensitivity, while its absence indicated resistance, irrespective of RAF/RAS status.
- Triple-negative breast cancer cell lines showed higher sensitivity.
- Acute myeloid leukemia and chronic myeloid leukemia cell lines were particularly sensitive.
Conclusions:
- Predictive biomarkers for GSK1120212 include RAF/RAS mutations and DUSP6 expression.
- GSK1120212 may benefit patients with RAF/RAS wild-type tumors, expanding its potential therapeutic indications.
- Further research into specific subtypes like triple-negative breast cancer is warranted.
