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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.
Abstract:
The MEK1 and MEK2 inhibitor GSK1120212 is currently in phase II/III clinical development. To identify predictive biomarkers, sensitivity to GSK1120212 was profiled for 218 solid tumor cell lines and 81 hematologic malignancy cell lines. For solid tumors, RAF/RAS mutation was a strong predictor of sensitivity. Among RAF/RAS mutant lines, co-occurring PIK3CA/PTEN mutations conferred a cytostatic response instead of a cytotoxic response for colon cancer cells that have the biggest representation of the comutations. Among KRAS mutant cell lines, transcriptomics analysis showed that cell lines with an expression pattern suggestive of epithelial-to-mesenchymal transition were less sensitive to GSK1120212. In addition, a proportion of cell lines from certain tissue types not known to carry frequent RAF/RAS mutations also seemed to be sensitive to GSK1120212. Among these were breast cancer cell lines, with triple negative breast cancer cell lines being more sensitive than cell lines from other breast cancer subtypes. We identified a single gene DUSP6, whose expression was associated with sensitivity to GSK1120212 and lack of expression associated with resistance irrelevant of RAF/RAS status. Among hematologic cell lines, acute myeloid leukemia and chronic myeloid leukemia cell lines were particularly sensitive. Overall, this comprehensive predictive biomarker analysis identified additional efficacy biomarkers for GSK1120212 in RAF/RAS mutant solid tumors and expanded the indication for GSK1120212 to patients who could benefit from this therapy despite the RAF/RAS wild-type status of their tumors.
Insights
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.
