The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
A Novel AKT1 Mutant Amplifies an Adaptive Melanoma Response to BRAF Inhibition
Open accessAbstract
BRAF inhibitor (BRAFi) therapy leads to remarkable anti melanoma responses, but the initial tumor shrinkage is commonly incomplete, providing a nidus for subsequent disease progression. Adaptive signaling may underlie early BRAFi resistance and influence the selection pattern for genetic variants, causing late, acquired resistance. We show here that BRAFi (or BRAFi + MEKi) therapy in patients frequently led to rebound phosphorylated AKT (p-AKT) levels in their melanomas early on-treatment. In cell lines, BRAFi treatment led to rebound levels of receptor tyrosine kinases (RTK; including PDGFRβ), phosphatidyl (3,4,5)-triphosphate (PIP3), pleckstrin homology domain recruitment, and p-AKT. PTEN expression limited this BRAFi-elicited PI3K–AKT signaling, which could be rescued by the introduction of a mutant AKT1 (Q79K) known to confer acquired BRAFi resistance. Functionally, AKT1Q79K conferred BRAFi resistance via amplification of BRAFi-elicited PI3K–AKT signaling. In addition, mitogen-activated protein kinase pathway inhibition enhanced clonogenic growth dependency on PI3K or AKT. Thus, adaptive or genetic upregulation of AKT critically participates in melanoma survival during BRAFi therapy. Significance: This study provides a mechanistic link between early, adaptive and late, acquired BRAF inhibitor resistance in melanoma, with early BRAFi-induced signaling alterations shaping the subsequent evolutionary selective pressure. These findings argue for upfront, combined targeting of the mutant BRAF genotype and a pervasive drug-adaptive, AKT-dependent tumor response. Cancer Discov; 4(1); 69–79. ©2013 AACR. See related commentary by Solit and Rosen, p. 27 This article is highlighted in the In This Issue feature, p. 1
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Mutations of the BRAF gene in human cancer
Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., et al. (2002) · Nature · doi:10.1038/nature00766 · Cited by 10,674
Improved survival with vemurafenib in melanoma with BRAF V600E mutation
Chapman, P. B., Hauschild, A., Robert, C., Haanen, J. B., Ascierto, P., Larkin, J., Dummer, R., Garbe, C., Testori, A., Maio, M., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1103782 · Cited by 7,720
Self-citationCombined BRAF and MEK inhibition in melanoma with BRAF V600 mutations
Flaherty, K. T., Infante, J. R., Daud, A., Gonzalez, R., Kefford, R. F., Sosman, J., Hamid, O., Schuchter, L., Cebon, J., Ibrahim, N., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1210093 · Cited by 2,810
Self-citationA landscape of driver mutations in melanoma
Hodis, E., Watson, I. R., Kryukov, G. V., Arold, S. T., Imielinski, M., Theurillat, J.-P., Nickerson, E., Auclair, D., Li, L., Place, C., et al. (2012) · Cell · doi:10.1016/j.cell.2012.06.024 · Cited by 2,610
Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib
Sosman, J. A., Kim, K. B., Schuchter, L., Gonzalez, R., Pavlick, A. C., Weber, J. S., McArthur, G. A., Hutson, T. E., Moschos, S. J., Flaherty, K. T., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1112302 · Cited by 2,156
Self-citationRAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)
Poulikakos, P. I., Persaud, Y., Janakiraman, M., Kong, X., Ng, C., Moriceau, G., Shi, H., Atefi, M., Titz, B., Gabay, M. T., et al. (2011) · Nature · doi:10.1038/nature10662 · Cited by 1,454
Self-citationModelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance
Das Thakur, M., Salangsang, F., Landman, A. S., Sellers, W. R., Pryer, N. K., Levesque, M. P., Dummer, R., McMahon, M., & Stuart, D. D. (2013) · Nature · doi:10.1038/nature11814 · Cited by 730
Cited by
PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer
Glaviano, A., Foo, A. S. C., Lam, H. Y., Yap, K. C. H., Jacot, W., Jones, R. H., Eng, H., Nair, M. G., Makvandi, P., Geoerger, B., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01827-6 · Cited by 2,138
Combined Vemurafenib and Cobimetinib in BRAF -Mutated Melanoma
Larkin, J., Ascierto, P. A., Dréno, B., Atkinson, V., Liszkay, G., Maio, M., Mandalà, M., Demidov, L., Stroyakovskiy, D., Thomas, L., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1408868 · Cited by 2,068
Self-citationPI3K/AKT signaling pathway and cancer: An updated review
Martini, M., De Santis, M. C., Braccini, L., Gulluni, F., & Hirsch, E. (2014) · Annals of Medicine · doi:10.3109/07853890.2014.912836 · Cited by 1,020
Acquired Resistance and Clonal Evolution in Melanoma during BRAF Inhibitor Therapy
Shi, H., Hugo, W., Kong, X., Hong, A., Koya, R. C., Moriceau, G., Chodon, T., Guo, R., Johnson, D. B., Dahlman, K. B., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0642 · Cited by 982
Self-citationLow MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma
Müller, J., Krijgsman, O., Tsoi, J., Robert, L., Hugo, W., Song, C., Kong, X., Possik, P. A., Cornelissen-Steijger, P. D. M., Foppen, M. H. G., et al. (2014) · Nature Communications · doi:10.1038/ncomms6712 · Cited by 639
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Metadata
- Authors
- Shi, H., Hong, A., Kong, X., Koya, R. C., Song, C., Moriceau, G., Hugo, W., Yu, C. C., Ng, C., Chodon, T., Scolyer, R. A., Kefford, R. F., Ribas, A., Long, G. V., & Lo, R. S.
- Venue
- Cancer Discovery
- Published
- 2014-01-01
- Volume
- 4
- Issue
- 1
- Pages
- 69-79
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2100969832
- Cited by
- 173
- References
- 7
- FWCI
- 8.88
- Type
- journal article
- Language
- en
- Open access
- green
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