Acute myeloid leukemia (AML) is a rapidly growing form of cancer in which the bone marrow massively overproduces immature blast cells, preventing production of normal blood cells. Research that provides insight into leukemogenesis and the mechanisms of drug action and drug resistance in AML cells should lead to better stratification and better therapeutic outcomes for patients. In this issue of Science Signaling, a pair of research articles found that AML cells depend on the DNA replication stress response. Using patient bioinformatics and cultured primary cells, David et al. found that the expression of the gene encoding the kinase CHK1, which correlated with protein abundance, was a predictive marker of poor prognosis in patients. Inhibiting CHK1 in cultured AML cells enhanced the efficacy of the currently used DNA replication inhibitor cytarabine. Using a mouse model of a particularly aggressive form of AML, Morgado-Palacin et al. found that inhibiting either ATR (a kinase upstream of CHK1 in the replication stress response) or ATM (a kinase in the DNA damage response pathway) reduced the growth of established cancer and prolonged animal survival. These drugs were effective as monotherapies, offering new hope to AML patients in whom the standard of care chemotherapy is ineffective.
An article in Science Signaling and one in Science Translational Medicine published in 2016 provide additional insights into drug targets and combinations that are useful in treating AML. Ishizawa et al. demonstrated that in AML the anticancer drug ONC201 had two mechanisms of action: (i) It triggered cell stress-mediated apoptosis by activating the transcription factor ATF4 and (ii) inhibited signaling by the kinase complex mTORC1, which promotes cell growth and proliferation. These details about ONC201’s mechanism of action may enable patient stratification and future development to improve its efficacy. Brumatti et al. showed that a drug that mimics the proapoptotic protein SMAC, birinapant, is particularly effective against AML when combined with inhibitors of caspase-mediated apoptosis. This combination causes cell death by necroptosis.
Last, research published in the 6 September 2016 issue of Science Signaling focuses attention on intercellular communication by exosomes as a target for therapeutic intervention. Hornick et al. discovered that exosomes released by AML cells not only reprogram the stem cell niche to block the production of healthy blood cells but also carry microRNAs that directly affect the hematopoietic stem cells. The severe anemia and thrombocytopenia that results from hematopoietic suppression is a major cause of morbidity in AML patients. Disrupting exosomal intercellular communication in the tumor microenvironment—a strategy of interest for many cancers—may reduce the need for bone marrow transplants in AML patients.
L. David, A. Fernandez-Vidal, S. Bertoli, S. Grgurevic, B. Lepage, D. Deshaies, N. Prade, M. Cartel, C. Larrue, J.-E. Sarry, E. Delabesse, C. Cazaux, C. Didier, C. Récher, S. Manenti, J.-S. Hoffmann, CHK1 as a therapeutic target to bypass chemoresistance in AML. Sci. Signal. 9, ra90 (2016). [Abstract]
I. Morgado-Palacin, A. Day, M. Murga, V. Lafarga, M. E. Anton, A. Tubbs, H.-T. Chen, A. Ergan, R. Anderson, A. Bhandoola, K. G. Pike, B. Barlaam, E. Cadogan, X. Wang, A. J. Pierce, C. Hubbard, S. A. Armstrong, A. Nussenzweig, O. Fernandez-Capetillo, Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML. Sci. Signal. 9, ra91 (2016). [Abstract]
J. Ishizawa, K. Kojima, D. Chachad, P. Ruvolo, V. Ruvolo, R. O. Jacamo, G. Borthakur,H. Mu,Z. Zeng, Y. Tabe, J. E. Allen, Z. Wang, W. Ma, H. C. Lee, R. Orlowski, D. D. Sarbassov, P. L. Lorenzi, X. Huang, S. S. Neelapu, T. McDonnell, R. N. Miranda, M. Wang, H. Kantarjian, M. Konopleva, R. E. Davis, M. Andreeff, ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies. Sci. Signal. 9, ra17 (2016). [Abstract]
G. Brumatti, C. Ma, N. Lalaoui, N.-Y. Nguyen, M. Navarro, M. C. Tanzer, J. Richmond, M. Ghisi, J. M. Salmon, N. Silke, G. Pomilio, S. P. Glaser, E. deValle, R. Gugasyan, M. A. Gurthridge, S. M. Condon, R. W. Johnstone, R. Lock, G. Salvesen, A. Wei, D. L. Vaux, P. G. Ekert, J. Silke, The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia. Sci. Transl. Med. 8, 339ra69 (2016). [Abstract]
N. I. Hornick, B. Doron, S. Abdelhamed, J. Huan, C. A. Harrington, R. Shen, X. A. Cambronne, S. Chakkaramakkil Verghese, P. Kurre, AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB. Sci. Signal. 9, ra88 (2016). [Abstract]