PI3′-Kinase Inhibition Forestalls the Onset of MEK1/2 Inhibitor Resistance in BRAF -Mutated Melanoma

Deuker, Marian M.; Marsh Durban, Victoria; Phillips, Wayne A.; McMahon, Martin

doi:10.1158/2159-8290.cd-14-0856

Cited by 68Melanoma and MAPK PathwaysPI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase Signaling

PI3′-Kinase Inhibition Forestalls the Onset of MEK1/2 Inhibitor Resistance in BRAF -Mutated Melanoma

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Deuker, Marian M., Marsh Durban, Victoria, Phillips, Wayne A., McMahon, Martin·2015·Cancer Discovery

DOI 10.1158/2159-8290.cd-14-0856PMC PMC4320669

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Abstract

Phosphatidylinositide 3′ (PI3′)-lipid signaling cooperates with oncogenic BRAFV600E to promote melanomagenesis. Sustained PI3′-lipid production commonly occurs via silencing of the PI3′-lipid phosphatase PTEN or, less commonly, through mutational activation of PIK3CA, encoding the 110-kDa catalytic subunit of PI3′-kinase-α (PI3Kα). To define the PI3K catalytic isoform dependency of BRAF-mutated melanoma, we used pharmacologic, isoform-selective PI3K inhibitors in conjunction with melanoma-derived cell lines and genetically engineered mouse (GEM) models. Although BRAFV600E/PIK3CAH1047R melanomas were sensitive to the antiproliferative effects of selective PI3Kα blockade, inhibition of BRAFV600E/PTENNull melanoma proliferation required combined blockade of PI3Kα, PI3Kδ, and PI3Kγ, and was insensitive to PI3Kβ blockade. In GEM models, isoform-selective PI3K inhibition elicited cytostatic effects, but significantly potentiated melanoma regression in response to BRAFV600E pathway–targeted inhibition. Interestingly, PI3K inhibition forestalled the onset of MEK inhibitor resistance in two independent GEM models of BRAFV600E-driven melanoma. These results suggest that combination therapy with PI3K inhibitors may be a useful strategy to extend the duration of clinical response of patients with BRAF-mutated melanoma to BRAFV600E pathway–targeted therapies. Significance: Although BRAFV600E pathway–targeted therapies elicit melanoma regression, the onset of drug resistance limits the durability of response. Here, we show that combined treatment with PI3K inhibitors significantly forestalled the onset of MEK1/2 inhibitor–resistant disease in BRAF-mutated GEM melanoma models. These results provide a conceptual framework for the combined deployment of BRAFV600E plus PI3K pathway–targeted inhibitors in the treatment of a subset of patients with BRAF-mutated melanoma. Cancer Discov; 5(2); 143–53. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 97

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The APOE variants exert cell-intrinsic effects on melanoma that impact primary tumor growth and metastatic capacity in a BrafV600E-driven GEMM.
“We reveal that the APOE variants exert cell-intrinsic effects on melanoma that impact primary tumor growth and metastatic capacity in a BrafV600E-driven GEMM, a model that has provided numerous important insights into melanoma biology (12,38–40).”
From Apolipoprotein E2 Stimulates Protein Synthesis and Promotes Melanoma Progression and Metastasis (2023) · cites this paper as [38]

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Additional file 7 of Diverse mechanisms activate the PI 3-kinase/mTOR pathway in melanomas: implications for the use of PI 3-kinase inhibitors to overcome resistance to inhibitors of BRAF and MEK
Tran, K. B., Kolekar, S., Jabed, A., Jaynes, P. W., Shih, J., Wang, Q., Flanagan, J. U., Rewcastle, G. W., Baguley, B. C., & Shepherd, P. R. (2021) · Figshare · doi:10.6084/m9.figshare.13727560
Additional file 1 of Diverse mechanisms activate the PI 3-kinase/mTOR pathway in melanomas: implications for the use of PI 3-kinase inhibitors to overcome resistance to inhibitors of BRAF and MEK
Tran, K. B., Kolekar, S., Jabed, A., Jaynes, P. W., Shih, J., Wang, Q., Flanagan, J. U., Rewcastle, G. W., Baguley, B. C., & Shepherd, P. R. (2021) · Figshare · doi:10.6084/m9.figshare.13727542
Additional file 5 of Diverse mechanisms activate the PI 3-kinase/mTOR pathway in melanomas: implications for the use of PI 3-kinase inhibitors to overcome resistance to inhibitors of BRAF and MEK
Tran, K. B., Kolekar, S., Jabed, A., Jaynes, P. W., Shih, J., Wang, Q., Flanagan, J. U., Rewcastle, G. W., Baguley, B. C., & Shepherd, P. R. (2021) · Figshare · doi:10.6084/m9.figshare.13727554
Additional file 6 of Diverse mechanisms activate the PI 3-kinase/mTOR pathway in melanomas: implications for the use of PI 3-kinase inhibitors to overcome resistance to inhibitors of BRAF and MEK
Tran, K. B., Kolekar, S., Jabed, A., Jaynes, P. W., Shih, J., Wang, Q., Flanagan, J. U., Rewcastle, G. W., Baguley, B. C., & Shepherd, P. R. (2021) · Figshare · doi:10.6084/m9.figshare.13727557
Additional file 8 of Diverse mechanisms activate the PI 3-kinase/mTOR pathway in melanomas: implications for the use of PI 3-kinase inhibitors to overcome resistance to inhibitors of BRAF and MEK
Tran, K. B., Kolekar, S., Jabed, A., Jaynes, P. W., Shih, J., Wang, Q., Flanagan, J. U., Rewcastle, G. W., Baguley, B. C., & Shepherd, P. R. (2021) · Figshare · doi:10.6084/m9.figshare.13727563
Additional file 4 of Diverse mechanisms activate the PI 3-kinase/mTOR pathway in melanomas: implications for the use of PI 3-kinase inhibitors to overcome resistance to inhibitors of BRAF and MEK
Tran, K. B., Kolekar, S., Jabed, A., Jaynes, P. W., Shih, J., Wang, Q., Flanagan, J. U., Rewcastle, G. W., Baguley, B. C., & Shepherd, P. R. (2021) · Figshare · doi:10.6084/m9.figshare.13727551
Additional file 2 of Diverse mechanisms activate the PI 3-kinase/mTOR pathway in melanomas: implications for the use of PI 3-kinase inhibitors to overcome resistance to inhibitors of BRAF and MEK
Tran, K. B., Kolekar, S., Jabed, A., Jaynes, P. W., Shih, J., Wang, Q., Flanagan, J. U., Rewcastle, G. W., Baguley, B. C., & Shepherd, P. R. (2021) · Figshare · doi:10.6084/m9.figshare.13727545
Additional file 3 of Diverse mechanisms activate the PI 3-kinase/mTOR pathway in melanomas: implications for the use of PI 3-kinase inhibitors to overcome resistance to inhibitors of BRAF and MEK
Tran, K. B., Kolekar, S., Jabed, A., Jaynes, P. W., Shih, J., Wang, Q., Flanagan, J. U., Rewcastle, G. W., Baguley, B. C., & Shepherd, P. R. (2021) · Figshare · doi:10.6084/m9.figshare.13727548
Palbociclib CDK4/6- and Crizotinib MET/ALK/ROS1-inhibitors Synergize to Enhance Senescence and Immune Recognition in Melanoma Cells Independently of BRAF / NRAS StatusPreprint
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Additional file 10 of Diverse mechanisms activate the PI 3-kinase/mTOR pathway in melanomas: implications for the use of PI 3-kinase inhibitors to overcome resistance to inhibitors of BRAF and MEK
Tran, K. B., Kolekar, S., Jabed, A., Jaynes, P., Shih, J.-H., Wang, Q., Flanagan, J. U., Rewcastle, G. W., Baguley, B. C., & Shepherd, P. R. (2021) · Figshare · doi:10.6084/m9.figshare.13727527
Additional file 14 of Diverse mechanisms activate the PI 3-kinase/mTOR pathway in melanomas: implications for the use of PI 3-kinase inhibitors to overcome resistance to inhibitors of BRAF and MEK
Tran, K. B., Kolekar, S., Jabed, A., Jaynes, P., Shih, J.-H., Wang, Q., Flanagan, J. U., Rewcastle, G. W., Baguley, B. C., & Shepherd, P. R. (2021) · Figshare · doi:10.6084/m9.figshare.13727539
Additional file 9 of Diverse mechanisms activate the PI 3-kinase/mTOR pathway in melanomas: implications for the use of PI 3-kinase inhibitors to overcome resistance to inhibitors of BRAF and MEK
Tran, K. B., Kolekar, S., Jabed, A., Jaynes, P., Shih, J.-H., Wang, Q., Flanagan, J. U., Rewcastle, G. W., Baguley, B. C., & Shepherd, P. R. (2021) · Figshare · doi:10.6084/m9.figshare.13727566
Additional file 11 of Diverse mechanisms activate the PI 3-kinase/mTOR pathway in melanomas: implications for the use of PI 3-kinase inhibitors to overcome resistance to inhibitors of BRAF and MEK
Tran, K. B., Kolekar, S., Jabed, A., Jaynes, P., Shih, J.-H., Wang, Q., Flanagan, J. U., Rewcastle, G. W., Baguley, B. C., & Shepherd, P. R. (2021) · Figshare · doi:10.6084/m9.figshare.13727530
Additional file 12 of Diverse mechanisms activate the PI 3-kinase/mTOR pathway in melanomas: implications for the use of PI 3-kinase inhibitors to overcome resistance to inhibitors of BRAF and MEK
Tran, K. B., Kolekar, S., Jabed, A., Jaynes, P., Shih, J.-H., Wang, Q., Flanagan, J. U., Rewcastle, G. W., Baguley, B. C., & Shepherd, P. R. (2021) · Figshare · doi:10.6084/m9.figshare.13727533
Additional file 13 of Diverse mechanisms activate the PI 3-kinase/mTOR pathway in melanomas: implications for the use of PI 3-kinase inhibitors to overcome resistance to inhibitors of BRAF and MEK
Tran, K. B., Kolekar, S., Jabed, A., Jaynes, P., Shih, J.-H., Wang, Q., Flanagan, J. U., Rewcastle, G. W., Baguley, B. C., & Shepherd, P. R. (2021) · Figshare · doi:10.6084/m9.figshare.13727536
Thérapies ciblées dans le mélanome : mécanismes impliqués dans les effets paradoxaux, les résistances et évaluation de nouvelles combinaisons
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Rôle de c-Jun dans la réponse aux inhibiteurs de la voie des MAPK dans les mélanomes
Pohorecka, M. (2018) · theses.fr (ABES) · doi:10.70675/4cf7db7bz9142z4de8zbcbbzd5860991d571

Characterizing the Role of PI3'-Kinase Signaling in BRAF-Mutated Melanoma
Deuker, M. M. (2015) · eScholarship (California Digital Library)
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Abstract IA29: PI3′ -kinase inhibition forestalls the onset of MEK1/2 inhibitor resistance in BRAFV600E/PTENNull melanoma
Deuker, M. M., Durban, V. M., Phillips, W. A., Silva, J. M., & McMahon, M. (2015) · Cancer Research · doi:10.1158/1538-7445.mel2014-ia29
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304 PI3′-Kinase inhibition forestalls the development of drug resistance in BRAFV600E/PTENNull melanoma
Deuker, M. M., Durban, V. M., Phillips, W. A., & McMahon, M. (2014) · European Journal of Cancer · doi:10.1016/s0959-8049(14)70430-7
Self-citation
Abstract B11: PI3-kinase inhibition forestalls the development of drug resistance in BRAFV600E/PTENNull melanoma
Deuker, M. M., Durban, V. M., Phillips, W. A., & McMahon, M. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1538-8514.pi3k14-b11
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Abstract SY17-03: Targeting BRAF and PI3′-kinase signaling for therapy of melanoma.
McMahon, M., Thakur, M. D., Marsh, V. L., Silva, J. M., Landman, A. S., Deuker, M. M., Salangsang, F., Pryer, N., Phillips, W. A., Levesque, M. P., et al. (2013) · Cancer Research · doi:10.1158/1538-7445.am2013-sy17-03
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Authors: Deuker, M. M., Marsh Durban, V., Phillips, W. A., & McMahon, M.
Affiliations: University of California, San Francisco (US)
1Helen Diller Family Comprehensive Cancer Center and Department of Cell and Molecular Pharmacology, University of California, San Francisco, San Francisco, California.
Peter MacCallum Cancer Centre (AU)
Corresponding author: McMahon, Martin
ORCID: Phillips, Wayne A.
McMahon, Martin
Venue: Cancer Discovery
Publisher: American Association for Cancer Research (AACR)
Published: 2015-02-01
Volume: 5
Issue: 2
Pages: 143-153
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-14-0856
PMC: PMC4320669
OpenAlex: W2136938899
Cited by: 60
References: 40
Citations by year: 2025: 1 · 2024: 4 · 2023: 2 · 2021: 14 · 2020: 4 · 2019: 5 · 2018: 5 · 2017: 11 · 2016: 5 · 2015: 9
FWCI: 3.42
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Cancer Discovery (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
Funders: National Cancer Institute (CA176839, R01CA176839)
National Institute of General Medical Sciences (T32GM064337)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: PI3K inhibition, BRAF-mutant melanoma, MEK inhibitor resistance, PI3Kα, PI3Kδ, PI3Kγ, PTEN loss, PIK3CA mutation, combination therapy, melanoma regression
MeSH terms: Animals, Carbamates, Humans, Melanoma, Melanoma, Experimental, Random Allocation, Sulfonamides, Thiazoles, MAP Kinase Signaling System, Cell Line, Tumor, Protein Kinase Inhibitors, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Proto-Oncogene Proteins B-raf, Cell Proliferation, PTEN Phosphohydrolase, Mice

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PI3′-Kinase Inhibition Forestalls the Onset of MEK1/2 Inhibitor Resistance in BRAF -Mutated Melanoma

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