PNNL

Abstract

Protective factors from the bone marrow microenvironment modulate responses to drug therapy. To examine the role of extrinsic factors in drug response, we performed an integrated analysis of primary specimens from over 300 acute myeloid leukemia (AML) patients with respect to secreted cytokine/growth factors, gene expression and ex vivo drug sensitivity to small molecule inhibitors. Among those cytokines with significant associations with specific ex vivo drug sensitivity profiles was CCL2 (MCP-1), high levels of which correlated with reduced sensitivity to the MEK1/2 inhibitor trametinib. This association was validated in trametinib-resistant AML cells. Global-phosphoproteomic analysis and genome-wide CRISPR/Cas9 screening revealed that CCL2 activates multiple pro-survival pathways including MAPK and cell cycle proteins. Combinatorial targeting of these pathways resulted in enhanced growth inhibition in AML cell models. Genetic and pharmacological inhibition of CCR2 also sensitized AML cells to trametinib. Our data demonstrate a novel role for CCL2 in resistance to MEK inhibition and identify combination strategies to overcome this resistance.