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

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Article number72
Pages1-11
Number of pages11
JournalOncogenesis
Volume7
Issue number9
DOIs
Publication statusPublished - 1 Sep 2018

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Mitogen-Activated Protein Kinase Kinases
Phosphatidylinositol 3-Kinases
Melanoma
Oncogenes
Neoplasms
Therapeutics
Survival
Population

Bibliographical note

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.

Cite this

Irvine, Mal ; Stewart, Ashleigh ; Pedersen, Bernadette ; Boyd, Suzanah ; Kefford, Richard ; Rizos, Helen. / Oncogenic PI3K/AKT promotes the step-wise evolution of combination BRAF/MEK inhibitor resistance in melanoma. In: Oncogenesis. 2018 ; Vol. 7, No. 9. pp. 1-11.
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Oncogenic PI3K/AKT promotes the step-wise evolution of combination BRAF/MEK inhibitor resistance in melanoma. / Irvine, Mal; Stewart, Ashleigh; Pedersen, Bernadette; Boyd, Suzanah; Kefford, Richard; Rizos, Helen.

In: Oncogenesis, Vol. 7, No. 9, 72, 01.09.2018, p. 1-11.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Stewart, Ashleigh

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AU - Kefford, Richard

AU - Rizos, Helen

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