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Updated: Jan 25, 2026
10:49
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
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Oral MEK 1/2 Inhibitor Trametinib in Combination With AKT Inhibitor GSK2141795 in Patients With Acute Myeloid
Brittany Knick Ragon1, Olatoyosi Odenike2, Maria R Baer3
1Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte, NC.
Clinical Lymphoma, Myeloma & Leukemia
|May 7, 2019
Summary
Combination therapy with MEK and AKT inhibitors showed no clinical activity in advanced acute myeloid leukemia (AML). While the treatment modulated key pathways, it did not lead to complete remissions in patients with RAS-mutated AML.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- MEK-1/2 inhibition shows promise in leukemia but faces resistance.
- Resistance mechanisms involve RAS/RAF hyperactivation or PI3K/AKT/mTOR pathway activation.
- Combination strategies are needed to overcome MEK inhibitor resistance.
Purpose of the Study:
- To evaluate the efficacy and safety of combining a MEK inhibitor (trametinib) with a pan-AKT inhibitor (GSK2141795).
- To assess the combination in patients with RAS-mutated relapsed/refractory acute myeloid leukemia (AML).
Main Methods:
- Phase II, multi-institution study of 23 patients with RAS-mutated AML.
- Two dose levels of trametinib and GSK2141795 were explored.
- Primary endpoint: proportion of patients achieving complete remission; secondary: toxicity and biologic effects.
Main Results:
- Dose level 1 was identified as the recommended phase II dose.
- No complete remissions were observed; 22% of patients had minor responses.
- Common toxicities included rash and diarrhea; dose-limiting toxicities were mucositis and colitis.
Conclusions:
- Combined MEK and AKT inhibition demonstrated no clinical activity in RAS-mutated AML.
- Pathway modulation (pERK, pS6) was observed, but did not translate to clinical benefit.
- Further research is needed to understand the disconnect between cellular activity and clinical outcomes.
Keywords:
AMLDevelopmental therapeuticsDrug resistanceNeoplasia-myeloid leukemias and dysplasiasPhase II clinical trialsMore Related Videos
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