Targeted agents, such as MEK inhibitors, may be incorporated into treatment; however, the impact of MEK inhibitors on the immune microenvironment in AML is not well understood.
Furthermore, we demonstrate that an AML cancer cell line harboring a lung adenocarcinoma-associated mutant SOS1 is dependent on <i>SOS1</i> for survival and is also sensitive to MEK inhibition.
This phase II multi-institution Cancer Therapy Evaluation Program-sponsored study was conducted to determine efficacy and safety of the combination of the ATP-competitive pan-AKT inhibitor GSK2141795, targeting the PI3K/AKT pathway, and the MEK inhibitor trametinib in RAS-mutated relapsed/refractory acute myeloid leukemia (AML).
Targeting of the RAS pathway has long been a critical therapeutic challenge in oncology.Burgess et al. examine how the relative expression of mutant and wild-type KRAS modulates clonal fitness and sensitivity to MEK inhibitors in a model of Kras<sup>G12D</sup> mutant acute myeloid leukemia and propose its use as a predictive biomarker.
Notably, <i>IDH/DNMT3A</i> double-mutant AMLs manifested upregulation of a RAS signaling signature and displayed unique sensitivity to MEK inhibition <i>ex vivo</i> as compared with AMLs with either single mutation.<b>Significance:</b> AML is biologically heterogeneous with subtypes characterized by specific genetic and epigenetic abnormalities.
As the genetic landscape of AML has been mapped, other attractive targets for therapy have been discovered, including C-KIT, IDH1 and IDH2, NPM1, and MEK.
Together, our data indicate that RAS-mutated myeloid leukemias are dependent on the PI3K isoform p110α, and combined pharmacologic inhibition of p110α and MEK could be an effective therapeutic strategy for JMML and AML.
These findings explain the phenomenon of peripheral blood versus bone marrow blast responses and suggest that the combination of potent FLT3 inhibition and MEK inhibition is a promising strategy for the treatment of FLT3-ITD AML.
Evaluation of the collateral mitogen-activated protein kinase (MAPK) pathway revealed a heterogeneous response to SYK inhibition in AML with downregulation of MEK and extracellular signal-regulated kinase (ERK) phosphorylation in some AML cell lines but a paradoxical increase in MEK/ERK phosphorylation in RAS-mutated AML.
Taken together, these results indicate that combined retinoid treatment and MEK blockade exert powerful antileukemic effects and could be developed into a novel therapeutic strategy for both AML and APL.