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Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Trametinib Sensitivity is Defined by a Myeloid Differentiation Profile in Acute Myeloid Leukemia
Mathieu Quesnel-Vallières1,2,3, David C Schultz1,4, Alena Orlenko4,5
1Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Background And Objective:
Acute myelogenous leukemia (AML) is a common blood cancer marked by heterogeneity in disease and diverse genetic abnormalities. Additional therapies are needed as the 5-year survival remains below 30%. Trametinib is a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor that is widely used in solid tumors and also in tumors with activating RAS mutations. A subset of patients with AML carry activating RAS mutations; however, a small-scale clinical trial with trametinib showed little efficacy. Here, we sought to identify transcriptomic determinants of trametinib sensitivity in AML.
Methods:
We tested the activity of trametinib against a panel of tumor cells from patients with AML ex vivo and compared this with RNA sequencing (RNA-Seq) data from untreated blasts from the same patient samples. We then used a correlation analysis between gene expression and trametinib sensitivity to identify potential biomarkers predictive of drug response.
Results:
We found that a subset of AML tumor cells were sensitive to trametinib ex vivo, only a fraction of which (3/10) carried RAS mutations. On the basis of our RNA-Seq analysis we found that markers of trametinib sensitivity are associated with a myeloid differentiation profile that includes high expression of CD14 and CLEC7A (Dectin-1), similar to the gene expression profile of monocytes. Further characterization confirmed that trametinib-sensitive samples display features of monocytic differentiation with high CD14 surface expression and were enriched for the M4 subtypes of the FAB classification.
Conclusions:
Our study identifies additional molecular markers that can be used with molecular features including RAS status to identify patients with AML that may benefit from trametinib treatment.
Insights
This study reveals that certain Acute Myelogenous Leukemia (AML) cells respond to trametinib, independent of RAS mutations. Monocytic differentiation markers like CD14 predict trametinib sensitivity in AML patients.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Acute Myelogenous Leukemia (AML) is a heterogeneous blood cancer with poor prognosis.
- Current therapies for AML are insufficient, necessitating novel treatment strategies.
- Trametinib, a MEK inhibitor, shows limited efficacy in AML despite its use in other cancers.
Purpose of the Study:
- To identify transcriptomic markers predicting trametinib sensitivity in AML.
- To explore novel therapeutic targets beyond RAS mutations in AML.
Main Methods:
- Ex vivo testing of trametinib activity on patient-derived AML cells.
- RNA sequencing (RNA-Seq) of AML blasts to correlate gene expression with drug sensitivity.
- Correlation analysis to identify predictive biomarkers for trametinib response.
Main Results:
- A subset of AML cells demonstrated sensitivity to trametinib ex vivo.
- Trametinib sensitivity was associated with monocytic differentiation markers (CD14, CLEC7A), not solely RAS mutations.
- Sensitive samples exhibited high CD14 expression and belonged to M4 FAB subtypes.
Conclusions:
- Identified novel molecular markers (CD14, CLEC7A) for predicting trametinib response in AML.
- Suggests trametinib may benefit AML patients with monocytic differentiation features.
- Highlights the need to consider transcriptomic profiles beyond RAS status for targeted AML therapy.
