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The MAPK pathway functions as a redundant survival signal that reinforces the PI3K cascade in c-Kit mutant melanoma

Oncogene volume 33, pages 236–245 (2014)Cite this article

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Abstract

Stimulation of the c-Kit receptor tyrosine kinase has a critical role in the development and migration of melanocytes, and oncogenic c-Kit mutants contribute to the progression of some melanomas. c-Kit signalling activates the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways and their relative contribution to the activities of oncogenic and ligand-dependent c-Kit remains uncertain. We show that PI3K is a major regulator of MAPK activation in response to c-Kit activity and the dominant effector of c-Kit-driven melanocyte proliferation and melanoma survival. Nevertheless, inhibition of the PI3K pathway in c-Kit mutant melanoma cells did not replicate the apoptotic efficacy of the c-Kit inhibitor, imatinib mesylate. Instead, the simultaneous suppression of the PI3K and MAPK pathways promoted a strong synergistic apoptotic effect. These data indicate that MAPK functions as a redundant survival signal that reinforces the PI3K cascade in c-Kit mutant melanoma. Thus, the concurrent inhibition of PI3K and MAPK signalling is required to suppress oncogenic c-Kit activity and may provide an effective therapeutic strategy in c-Kit mutant melanomas.

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Acknowledgements

We are grateful to Antoni Ribas, Peter Hersey and Meenhard Herlyn for providing c-Kit mutant melanoma cells lines. This work is supported by Programme Grant 633004 and project grants of the National Health and Medical Research Council of Australia (NHMRC) and an infrastructure grant to Westmead Millennium Institute by the Health Department of NSW through Sydney West Area Health Service. Westmead Institute for Cancer Research is the recipient of capital grant funding from the Australian Cancer Research Foundation. HR is a recipient of a Cancer Institute New South Wales, Research Fellowship and a NHMRC Senior Research Fellowship. JT is supported by an Australian Postgraduate Award and a Westmead Medical Research Foundation Top-up Award. The support of the Melanoma Foundation of the University of Sydney and colleagues from Melanoma Institute Australia and the Department of Anatomical Pathology at the Royal Prince Alfred Hospital are also gratefully acknowledged.

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Authors and Affiliations

  1. Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales, Australia

    J R Todd, L L Scurr, T M Becker, R F Kefford & H Rizos

  2. Melanoma Institute Australia, Sydney, New South Wales, Australia

    R F Kefford

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Todd, J., Scurr, L., Becker, T. et al. The MAPK pathway functions as a redundant survival signal that reinforces the PI3K cascade in c-Kit mutant melanoma. Oncogene 33, 236–245 (2014). https://doi.org/10.1038/onc.2012.562

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