Sensitivity analysis of the NPM-ALK signalling network reveals important pathways for anaplastic large cell lymphoma combination therapy

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Abstract

A large subset of anaplastic large cell lymphoma (ALCL) patients harbour a somatic aberra-tion in which anaplastic lymphoma kinase (ALK) is fused to nucleophosmin (NPM) resulting in a constitutively active signalling fusion protein, NPM-ALK. We computationally simulated the signalling network which mediates pathological cell survival and proliferation through NPM-ALK to identify therapeutically targetable nodes through which it may be possible to regain control of the tumourigenic process. The simulations reveal the predominant role of the VAV1-CDC42 (cell division control protein 42) pathway in NPM-ALK-driven cellular pro-liferation and of the Ras / mitogen-activated ERK kinase (MEK) / extracellular signal-regu-lated kinase (ERK) cascade in controlling cell survival. Our results also highlight the importance of a group of interleukins together with the Janus kinase 3 (JAK3) / signal trans-ducer and activator of transcription 3 (STAT3) signalling in the development of NPM-ALK derived ALCL. Depending on the activity of JAK3 and STAT3, the system may also be sen-sitive to activation of protein tyrosine phosphatase-1 (SHP1), which has an inhibitory effect on cell survival and proliferation. The identification of signalling pathways active in tumouri-genic processes is of fundamental importance for effective therapies. The prediction of alternative pathways that circumvent classical therapeutic targets opens the way to preven-tive approaches for countering the emergence of cancer resistance.

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Buetti-Dinh, A., O’Hare, T., & Friedman, R. (2016). Sensitivity analysis of the NPM-ALK signalling network reveals important pathways for anaplastic large cell lymphoma combination therapy. PLoS ONE, 11(9). https://doi.org/10.1371/journal.pone.0163011

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