Targeting c-FOS and DUSP1 abrogates intrinsic resistance to tyrosine-kinase inhibitor therapy in BCR-ABL-induced leukemia.

Abstract

Tyrosine kinase inhibitor (TKI) therapy for human cancers is not curative, with relapse due to the continuing presence of tumor cells, referred to as minimal residual disease (MRD) cells. MRD stem or progenitor cells survival in the absence of oncogenic kinase signaling, a phenomenon referred to as intrinsic resistance, depends on diverse growth factors. Here, we report that oncogenic kinase and growth factor signaling converge to induce the expression of the signaling proteins c-Fos and Dusp1. Genetic deletion of c-Fos and Dusp1 suppressed tumor growth in a BCR-ABL-induced mouse model of chronic myeloid leukemia (CML). Pharmacological inhibition of c-Fos, Dusp1 and BCR-ABL eradicated MRD in multiple in vivo models, as well as in primary CML patient xenotransplanted mice. Growth factor signaling also conferred TKI resistance and induced c-FOS and DUSP1 expression in tumor cells modeling other types of kinase-driven leukemias. Our data demonstrate that c-Fos and Dusp1 expression levels determine the threshold of TKI efficacy, such that growth factor-induced expression of c-Fos and Dusp1 confers intrinsic resistance to TKI therapy in a wide-ranging set of leukemias, and may represent a unifying Achilles heel of kinase-driven cancers.