Abstract
Tyrosine-kinase inhibitor (TKI) therapy for human cancers is not curative, and relapse occurs owing to the continued presence of tumor cells, referred to as minimal residual disease (MRD). The survival of MRD stem or progenitor cells 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 FBJ osteosarcoma oncogene (c-FOS, encoded by Fos) and dual-specificity phosphatase 1 (DUSP1). Genetic deletion of Fos and Dusp1 suppressed tumor growth in a BCR-ABL fusion protein kinase–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 mice xenotransplanted with patient-derived primary CML cells. Growth-factor signaling also conferred TKI resistance and induced 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 might represent a unifying Achilles' heel of kinase-driven cancers.
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Acknowledgements
The authors are thankful to H. Singh and Y. Zheng for providing critical feedback on this study. We are thankful to G. Daley for providing the BaF3-BA cells and T. Reya for the MSCV-BCR-ABL-Ires-YFP constructs. We are thankful to M. Carroll for providing the patient samples from the CML blast crisis. This study was supported by grants to M.A. from the NCI (1RO1CA155091), Leukemia Research Foundation and V Foundation and from the NHLBI (R21HL114074-01).
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Experiments were conceived and designed by M.K. and M.A. Experiments were performed by M.K., Z.K., A.G., E.H., S.R, Z.S., M.F.B., T.L., M.X., J.C.M., J.A.C., and H.L.G. Bioinformatics analysis of microarrays and RNA-seq data were performed by M.K. and K.K. The manuscript was written by M.K. and M.A.
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Kesarwani, M., Kincaid, Z., Gomaa, A. et al. Targeting c-FOS and DUSP1 abrogates intrinsic resistance to tyrosine-kinase inhibitor therapy in BCR-ABL-induced leukemia. Nat Med 23, 472–482 (2017). https://doi.org/10.1038/nm.4310
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DOI: https://doi.org/10.1038/nm.4310
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