Oncogenic PI3K/AKT promotes the step-wise evolution of combination BRAF/MEK inhibitor resistance in melanoma

Mal Irvine, Ashleigh Stewart, Bernadette Pedersen, Suzanah Boyd, Richard Kefford, Helen Rizos*

*Corresponding author for this work

Research output: Contribution to journalArticle

7 Citations (Scopus)
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Abstract

Nearly all patients with BRAF-mutant melanoma will progress on BRAF inhibitor monotherapy and combination BRAF/MEK inhibitor therapy within the first year of therapy. In the vast majority of progressing melanomas, resistance occurs via the re-activation of MAPK signalling, commonly via alterations in BRAF, NRAS and MEK1/2. A small proportion of resistant melanomas rely on the activation of the compensatory PI3K/AKT signalling cascade, although activation of this pathway does not preclude patient responses to BRAF/MEK inhibition. We now show, that PI3K/AKT signalling via potent oncogenic PIK3CA and AKT3 mutants, is not sufficient to overcome proliferative arrest induced by BRAF/MEK inhibition, but rather enables the survival of a dormant population of MAPK-inhibited melanoma cells. The evolution of resistance in these surviving tumour cells was associated with MAPK re-activation and no longer depended on the initial PI3K/AKT-activating oncogene. This dynamic form of resistance alters signalling dependence and may lead to the evolution of tumour subclones highly resistant to multiple targeted therapies.

Original languageEnglish
Article number72
Pages (from-to)1-11
Number of pages11
JournalOncogenesis
Volume7
Issue number9
DOIs
Publication statusPublished - 1 Sep 2018

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Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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