Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations - PubMed (original) (raw)
Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations
James G Greger et al. Mol Cancer Ther. 2012 Apr.
Abstract
Recent results from clinical trials with the BRAF inhibitors GSK2118436 (dabrafenib) and PLX4032 (vemurafenib) have shown encouraging response rates; however, the duration of response has been limited. To identify determinants of acquired resistance to GSK2118436 and strategies to overcome the resistance, we isolated GSK2118436 drug-resistant clones from the A375 BRAF(V600E) and the YUSIT1 BRAF(V600K) melanoma cell lines. These clones also showed reduced sensitivity to the allosteric mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor GSK1120212 (trametinib). Genetic characterization of these clones identified an in-frame deletion in MEK1 (MEK1(K59del)) or NRAS mutation (NRAS(Q61K) and/or NRAS(A146T)) with and without MEK1(P387S) in the BRAF(V600E) background and NRAS(Q61K) in the BRAF(V600K) background. Stable knockdown of NRAS with short hairpin RNA partially restored GSK2118436 sensitivity in mutant NRAS clones, whereas expression of NRAS(Q61K) or NRAS(A146T) in the A375 parental cells decreased sensitivity to GSK2118436. Similarly, expression of MEK1(K59del), but not MEK1(P387S), decreased sensitivity of A375 cells to GSK2118436. The combination of GSK2118436 and GSK1120212 effectively inhibited cell growth, decreased ERK phosphorylation, decreased cyclin D1 protein, and increased p27(kip1) protein in the resistant clones. Moreover, the combination of GSK2118436 or GSK1120212 with the phosphoinositide 3-kinase/mTOR inhibitor GSK2126458 enhanced cell growth inhibition and decreased S6 ribosomal protein phosphorylation in these clones. Our results show that NRAS and/or MEK mutations contribute to BRAF inhibitor resistance in vitro, and the combination of GSK2118436 and GSK1120212 overcomes this resistance. In addition, these resistant clones respond to the combination of GSK2126458 with GSK2118436 or GSK1120212. Clinical trials are ongoing or planned to test these combinations.
©2012 AACR.
Similar articles
- Aberrant modulation of ribosomal protein S6 phosphorylation confers acquired resistance to MAPK pathway inhibitors in BRAF-mutant melanoma.
Gao MZ, Wang HB, Chen XL, Cao WT, Fu L, Li Y, Quan HT, Xie CY, Lou LG. Gao MZ, et al. Acta Pharmacol Sin. 2019 Feb;40(2):268-278. doi: 10.1038/s41401-018-0020-z. Epub 2018 May 18. Acta Pharmacol Sin. 2019. PMID: 29777202 Free PMC article. - Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway.
Atefi M, von Euw E, Attar N, Ng C, Chu C, Guo D, Nazarian R, Chmielowski B, Glaspy JA, Comin-Anduix B, Mischel PS, Lo RS, Ribas A. Atefi M, et al. PLoS One. 2011;6(12):e28973. doi: 10.1371/journal.pone.0028973. Epub 2011 Dec 14. PLoS One. 2011. PMID: 22194965 Free PMC article. - Combinatorial treatments that overcome PDGFRβ-driven resistance of melanoma cells to V600EB-RAF inhibition.
Shi H, Kong X, Ribas A, Lo RS. Shi H, et al. Cancer Res. 2011 Aug 1;71(15):5067-74. doi: 10.1158/0008-5472.CAN-11-0140. Cancer Res. 2011. PMID: 21803746 Free PMC article. - Dabrafenib and its potential for the treatment of metastatic melanoma.
Menzies AM, Long GV, Murali R. Menzies AM, et al. Drug Des Devel Ther. 2012;6:391-405. doi: 10.2147/DDDT.S38998. Epub 2012 Dec 11. Drug Des Devel Ther. 2012. PMID: 23251089 Free PMC article. Review. - Targeting oncogenic Raf protein-serine/threonine kinases in human cancers.
Roskoski R Jr. Roskoski R Jr. Pharmacol Res. 2018 Sep;135:239-258. doi: 10.1016/j.phrs.2018.08.013. Epub 2018 Aug 15. Pharmacol Res. 2018. PMID: 30118796 Review.
Cited by
- Genotyping of cutaneous melanoma.
Glitza IC, Davies MA. Glitza IC, et al. Chin Clin Oncol. 2014 Sep;3(3):27. doi: 10.3978/j.issn.2304-3865.2014.03.01. Chin Clin Oncol. 2014. PMID: 25632386 Free PMC article. - Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance.
McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Franklin RA, Montalto G, Cervello M, Libra M, Candido S, Malaponte G, Mazzarino MC, Fagone P, Nicoletti F, Bäsecke J, Mijatovic S, Maksimovic-Ivanic D, Milella M, Tafuri A, Chiarini F, Evangelisti C, Cocco L, Martelli AM. McCubrey JA, et al. Oncotarget. 2012 Oct;3(10):1068-111. doi: 10.18632/oncotarget.659. Oncotarget. 2012. PMID: 23085539 Free PMC article. Review. - Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade.
Yan C, Saleh N, Yang J, Nebhan CA, Vilgelm AE, Reddy EP, Roland JT, Johnson DB, Chen SC, Shattuck-Brandt RL, Ayers GD, Richmond A. Yan C, et al. Mol Cancer. 2021 Jun 6;20(1):85. doi: 10.1186/s12943-021-01366-y. Mol Cancer. 2021. PMID: 34092233 Free PMC article. - Aurora kinase A revives dormant laryngeal squamous cell carcinoma cells via FAK/PI3K/Akt pathway activation.
Yang LY, He CY, Chen XH, Su LP, Liu BY, Zhang H. Yang LY, et al. Oncotarget. 2016 Jul 26;7(30):48346-48359. doi: 10.18632/oncotarget.10233. Oncotarget. 2016. PMID: 27356739 Free PMC article. - Progression of cutaneous melanoma: implications for treatment.
Leong SP, Mihm MC Jr, Murphy GF, Hoon DS, Kashani-Sabet M, Agarwala SS, Zager JS, Hauschild A, Sondak VK, Guild V, Kirkwood JM. Leong SP, et al. Clin Exp Metastasis. 2012 Oct;29(7):775-96. doi: 10.1007/s10585-012-9521-1. Epub 2012 Aug 15. Clin Exp Metastasis. 2012. PMID: 22892755 Free PMC article. Review.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials
Miscellaneous