Editors' ChoiceCancer

Paths to Resistance

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Science Signaling  22 Sep 2009:
Vol. 2, Issue 89, pp. ec311
DOI: 10.1126/scisignal.289ec311

The development of drug resistance limits the effectiveness of cancer therapies. Lauchle et al. investigated the effectiveness of a drug (CI-1040) that inhibits mitogen-activated protein kinase kinase (MEK) in a mouse model of a myeloproliferative disorder caused by excessive activity of the Ras-MEK-ERK (extracellular signal–regulated protein kinase) cascade and that, in the presence of additional mutations, progresses to leukemia. Inactivation of the tumor suppressor neurofibromin (Nf1), which encodes a guanosine triphosphatase (GTPase)–activating protein for Ras, initiates the myeloproliferative disorder. CI-1040 was ineffective at reducing colony formation of cells isolated from the mice with the myeloproliferative disorder but decreased colony formation of cells from the mice that had developed acute myeloid leukemia (AML) due to retroviral-induced mutagenesis. CI-1040 was initially effective at reducing blood leukocyte counts when AML cells were transplanted into recipient mice, but ultimately all recipients died from recurrence of the leukemia. Clonal analysis of two of the parental drug-sensitive AMLs and the resistant leukemias that developed after drug treatment of the mice revealed that mutations in Rasgrp1, which encodes a Ras guanine nucleotide exchange protein that increases the activity of Ras, and Mapk14, which encodes the stress-activated MAPK p38α, were associated with drug resistance. Transcripts for Rasgrp1 were increased and Ras-GTP was increased in the resistant cells from the one AML parent, whereas one allele of Mapk14 was inactivated and p38α activity was reduced in the resistant cells derived from another parent AML. Thus, disease progression involves the initial loss of the tumor suppressor causing the myeloproliferative disorder, followed by additional mutations that produce AML and render the cells more dependent on Ras-MAPK signaling. Then, after drug treatment to block the hyperactive Ras-MAPK pathway, relapse occurs when the cells develop mutations that allow the cells to either overcome the signaling block (increased Rasgrp1 activity) or prevent proapoptotic signals (reduced p38α). Understanding the molecular nature of this disease and resistance process has fundamental implications for cancer therapy strategies.

J. O. Lauchle, D. Kim, D. T. Le, K. Akagi, M. Crone, K. Krisman, K. Warner, J. M. Bonifas, Q. Li, K. M. Coakley, E. Diaz-Flores, M. Gorman, S. Przybranowski, M. Tran, S. C. Kogan, J. P. Roose, N. G. Copeland, N. A. Jenkins, L. Parada, L. Wolff, J. Sebolt-Leopold, K. Shannon, Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. Nature 461, 411–414 (2009). [PubMed]

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