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Please use this identifier to cite or link to this item: http://hdl.handle.net/1959.14/340749
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- Title
- The MAPK pathway functions as a redundant survival signal that reinforces the PI3K cascade in c-Kit mutant melanoma
- Related
- Oncogene, Vol. 33, No. 2, (2014), p.236-245
- Funding Body
- NHMRC
- Grant URL
- http://purl.org/au-research/grants/nhmrc/633004
- Grant URL
- http://purl.org/au-research/grants/nhmrc/1003314
- DOI
- 10.1038/onc.2012.562
- Publisher
- Nature Publishing Group
- Date
- 2014
- Author/Creator
- Todd, J. R
- Author/Creator
- Scurr, L. L
- Author/Creator
- Becker, T. M
- Author/Creator
- Kefford, R. F
- Author/Creator
- Rizos, H
- Description
- 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.
- Description
- 10 page(s)
- Subject Keyword
- c-Kit
- Subject Keyword
- MAPK
- Subject Keyword
- melanocytes
- Subject Keyword
- melanoma
- Subject Keyword
- PI3K
- Subject Keyword
- stem cell factor
- Resource Type
- journal article
- Organisation
- Macquarie University. Australian School of Advanced Medicine
- Identifier
- http://hdl.handle.net/1959.14/340749
- Identifier
- mq:37834
- Identifier
- ISSN:0950-9232
- Identifier
- mq-rm-2013010691
- Identifier
- mq_res-ext-2-s2.0-84891932035
- Language
- eng
- Reviewed
Macquarie University ResearchOnline
