Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K

Villanueva, Jessie; Vultur, Adina; Lee, John Tayu; Somasundaram, Rajasekharan; Fukunaga-Kalabis, Mizuho; Cipolla, Angela K.; Wubbenhorst, Bradley; Xu, Xiaowei; Gimotty, Phyllis A.; Kee, Damien; Santiago-Walker, Ademi; Letrero, Richard; D’Andrea, Kurt; Pushparajan, Anitha; Hayden, James; Brown, Kimberly Dahlman; Laquerre, Sylvie; McArthur, Grant A.; Sosman, Jeffrey A.; Nathanson, Katherine L.; Herlyn, Meenhard

doi:10.1016/j.ccr.2010.11.023

Cited by 1,144 publications

(1,154 citation statements)

References 43 publications

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“…This is the basis of the high therapeutic index of these drugs, but RAF dimerization is also predicted to result in drug resistance Samatar and Poulikakos, 2014). Indeed, mechanisms that result in increased RAF dimerization, such as upregulation of receptor tyrosine kinases (RTK) signaling, RAS mutation, BRAF amplification and expression of splice variants of BRAF V600E were reported to be responsible for clinical resistance to RAF inhibitors (Corcoran et al, 2011;Nazarian et al, 2010;Poulikakos et al, 2011;Shi et al, 2012;Villanueva et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling

Karoulia¹,

Wu²,

Ahmed³

et al. 2016

Cancer Cell

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127

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SUMMARYThe complex biochemical effects of RAF inhibitors account for both the effectiveness and mechanisms of resistance to these drugs, but a unified mechanistic model has been lacking. HereCorrespondence and requests for materials should be addressed to: Poulikos.poulikakos@mssm.edu or evripidis.gavathiotis@einstein.yu.edu. * These authors contributed equally to this work Accession numbers. Structural coordinates and parameters have been submitted to the Protein Database Bank under the following accession codes: 4RZV for BRAF R509H /VEM, 4RZW for BRAF R509H /AZ and 5ITA for BRAF WT /AZ-VEM. Other structural coordinates used in this study are the following: PDB ID: 4KSP for TAK bound to BRAF dimer, PDB ID: 3OG7 for VEM bound to BRAF V600E dimer, PDB ID: 4MNF for GDC bound to BRAF V600E dimer, PDB ID: 2FB8 for SB bound to BRAF dimer, PDB ID: 4XV2 for DAB bound to BRAF V600E dimer and PDB ID: 4XV1 for PB bound to BRAF V600E dimer and PDB 4MNE for the BRAF/MEK complex. AUTHOR CONTRIBUTIONSP.I.P., E.G., C.K., M.H., A.L., Z.K., Y.W. and T.A.A designed experiments. Z.K., T.A.A conducted biochemical and cellular studies. E.G., Y.W. performed structural determination and structural analysis. X.W. generated the CRAF-V5 CRISPR cell line. Q.X. synthesized the AZ-VEM compound. C.K., M.H., J.A.F., A.L., E.G., P.I.P. designed animal studies. Z.K., T.A.A and J.B. conducted animal experiments. C.Z. and G.B. provided reagents and analyzed data. P.I.P. and E.G. designed research, analyzed data and wrote the manuscript, which was edited by all authors.C.Z. and G.B. are employees of Plexxikon Inc. All other authors declare no competing financial interests.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. we show that RAF inhibitors exert their effects via two distinct allosteric mechanisms. Drug resistance due to dimerization is determined by the position of the αC-helix stabilized by inhibitor, whereas inhibitor-induced RAF priming and dimerization are the result of inhibitor-induced formation of the RAF/RAS-GTP complex. The biochemical effect of RAF inhibitor in cells is the combined outcome of the two mechanisms. Therapeutic strategies including αC-helix-IN inhibitors are more effective in multiple mutant BRAF-driven tumor models, including colorectal and thyroid BRAF V600E cancers, in which first generation RAF inhibitors have been ineffective. HHS Public Access

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Section: Introductionmentioning

confidence: 99%

An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling

Karoulia¹,

Wu²,

Ahmed³

et al. 2016

Cancer Cell

Self Cite

127

View full text Add to dashboard Cite

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“…5,24), with recent clinical studies reporting that highly specific BRAF inhibitors are effective in the treatment of metastatic melanoma (25)(26)(27). However, initial promise has been hampered by the development of resistance (28)(29)(30), which is characterized by the reactivation of ERK1/2 (31)(32)(33) and has been attributed to various mechanisms including activating NRAS mutations (29), CRAF overexpression (34), compensatory upregulation of MAP2K kinase COT (28), activating MEK1 mutations (35), and amplification of mutant BRAF (36).…”

Section: Introductionmentioning

confidence: 99%

Isolation of a Novel Thioflavin S–Derived Compound That Inhibits BAG-1–Mediated Protein Interactions and Targets BRAF Inhibitor–Resistant Cell Lines

Enthammer

Papadakis

Gachet

et al. 2013

Molecular Cancer Therapeutics

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Protein-protein interactions mediated through the C-terminal Bcl-2-associated athanogene (BAG) domain of BAG-1 are critical for cell survival and proliferation. Thioflavin S (NSC71948)-a mixture of compounds resulting from the methylation and sulfonation of primulin base-has been shown to dosedependently inhibit the interaction between BAG-1 and Hsc70 in vitro. In human breast cancer cell lines, with high BAG-1 expression levels, Thioflavin S reduces the binding of BAG-1 to Hsc70, Hsp70, or CRAF and decreases proliferation and viability. Here, we report the development of a protocol for the purification and isolation of biologically active constituents of Thioflavin S and the characterization of the novel compound Thio-2. Thio-2 blocked the growth of several transformed cell lines, but had much weaker effects on untransformed cells. Thio-2 also inhibited the proliferation of melanoma cell lines that had become resistant to treatment with PLX4032, an inhibitor of mutant BRAF. In transformed cells, Thio-2 interfered with intracellular signaling at the level of RAF, but had no effect on the activation of AKT. Thio-2 decreased binding of BAG-1 to Hsc70 and to a lesser extent BRAF in vitro and in vivo, suggesting a possible mechanism of action. Given that tumors frequently develop resistance to kinase inhibitors during treatment, Thio-2 and related compounds may offer promising alternative strategies to currently available therapies.

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“…Several mechanisms of resistance to B-Raf inhibitors have been described in melanoma, such as activation of PI3 K and COT pathways, and N-Ras mutations (Villanueva et al, 2010;Nazarian et al, 2010;Johannessen et al, 2010). By activating parallel pathways involved in cell growth, cancer cells are able to overcome the blockade at MAPK pathway.…”

Section: Overcoming Resistancementioning

confidence: 99%

BRAF mutations in non-small cell lung cancer: has finally Janus opened the door?

Caparica

Castro

Gil-Bazo

et al. 2016

Critical Reviews in Oncology/Hematology

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Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K

Cited by 1,144 publications

References 43 publications

An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling

An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling

Isolation of a Novel Thioflavin S–Derived Compound That Inhibits BAG-1–Mediated Protein Interactions and Targets BRAF Inhibitor–Resistant Cell Lines

BRAF mutations in non-small cell lung cancer: has finally Janus opened the door?

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