Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers

Peng, Sheng-Bin; Henry, James R.; Kaufman, Michael D.; Lu, Wange; Smith, Bryan D.; Vogeti, Subha; Rutkoski, Thomas J.; Wise, Scott; Chun, Lawrence; Zhang, Youyan; Horn, Robert D. Van; Yin, Tinggui; Zhang, Xiaoyi; Yadav, Vipin; Chen, Shih-Hsun; Gong, Xueqian; Ma, Xiwen; Webster, Yue; Buchanan, Sean G.; Mochalkin, Igor; Huber, Lysiane; Kays, Lisa; Donoho, Gregory P.; Walgren, Jennie; McCann, Denis; Patel, Phenil J.; Conti, Ilaria; Plowman, Gregory D.; Starling, James J.; Flynn, Daniel L.

doi:10.1016/j.ccell.2015.08.002

Cited by 268 publications

(341 citation statements)

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“…While in the post-sorafenib era the main goal had been to gain specificity towards mutated BRAF lately some effort has been put towards the development of small molecules directed to both BRAF and CRAF and capable to interfere with isoform hetero-and homo-dimerization thus preventing paradoxical activation of CRAF by BRAF inhibitors (72,(105)(106)(107)(108)(109)(110). While this approach has provided promising results in pre-clinical models, their efficacy and the risk of adverse events will have to be tested in early phase trials (NCT02607813, www.clinicaltrials.gov).…”

Section: Potential For Alternative Combination Therapiesmentioning

confidence: 99%

Overcoming resistance to BRAF inhibitors

2017

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Abstract:The discovery of activating mutations in the serine/threonine (S/T) kinase BRAF followed by a wave of follow-up research manifested that the MAPK-pathway plays a critical role in melanoma initiation and progression. BRAF and MEK inhibitors produce an unparalleled response rate in melanoma, but it is now clear that most responses are transient, and while some patients show long lasting responses the majority progress within 1 year. In accordance with the key role played by the MAPK-pathway in BRAF mutant melanomas, disease progression is mostly due to the appearance of drug-resistance mechanisms leading to restoration of MAPK-pathway activity. In the present article we will review the development, application and clinical effects of BRAF and MEK inhibitors both, as single agent and in combination in the context of targeted therapy in melanoma. We will then describe the most prominent mechanisms of resistance found in patients progressed on these targeted therapies. Finally we will discuss strategies for further optimizing the use of MAPK inhibitors and will describe the potential of alternative combination therapies to either delay the onset of resistance to MAPK inhibitors or directly target specific mechanisms of resistance to BRAF/ MEK inhibitors.

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Section: Potential For Alternative Combination Therapiesmentioning

confidence: 99%

Overcoming resistance to BRAF inhibitors

2017

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“…To identify potent inhibitors of dimeric BRAF, we compared eight structurally diverse RAF inhibitors: AZ-628 (AZ) (McDermott et al, 2007), TAK-632 (TAK) , LY3009120 (LY) (Peng et al, 2015), GDC-0879 (GDC) (Hoeflich et al, 2009), SB-590885 (SB) (King et al, 2006), PLX7904/Paradox Breaker (PB), which does not to induce paradoxical activation in wild-type BRAF cells , Vemurafenib (VEM) and Dabrafenib (DAB) (Rheault et al, 2013) (Figure S1A, Table S1). To compare potencies of inhibitors in cells endogenously expressing monomeric or dimeric BRAF V600E , we treated parental (PAR) SKMEL239 cells expressing full length BRAF V600E and the SKMEL239 derivative (clone C3) that is resistant to VEM due to enhanced dimerization of endogenous splice variants of BRAF V600E that lack the RAS-binding domain (Poulikakos et al, 2011).…”

Section: Structurally Diverse Raf Inhibitors Equi-potently Inhibit Momentioning

confidence: 99%

“…In cells with BRAF WT they paradoxically activate RAF and ERK signaling, via a RASdependent mechanism that remains incompletely understood. Recently, a number of RAF inhibitors with diverse structural and biochemical properties entered preclinical and clinical development Peng et al, 2015;Zhang et al, 2015). We sought to develop an integrated model of RAF inhibitor action that would explain the biochemical effects of RAF inhibitors based on their structural properties in any cellular context.…”

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

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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“…Recently, next generation RAF inhibitors were identified and characterized in vitro and in vivo in xenografts [Girotti et al 2015;Peng et al 2015;Yao et al 2015;Zhang et al 2015]. These drugs are called paradox-breaking RAF inhibitors because they suppress mutant BRAF cells without activating the MAPK pathway in cells bearing WT BRAF or upstream activation by mutated RAS.…”

Section: Overcoming Resistance To Braf Inhibitorsmentioning

confidence: 99%

“…Peng and colleagues and Girotti and colleagues characterized new pan-RAF inhibitors with minimal paradoxical pathway activation in BRAF WT or RAS mutant cells [Girotti et al 2015;Peng et al 2015]. These pan-RAF compounds inhibit ARAF, BRAF and CRAF isoforms with high affinity and are active in BRAF mutant cells, first generation BRAF TKI resistant cells, as well as RAS mutant cells with or without a co-occurring BRAF mutation.…”

Section: Overcoming Resistance To Braf Inhibitorsmentioning

confidence: 99%

Therapeutic approach to treating patients with BRAF-mutant lung cancer: latest evidence and clinical implications

Langen

Smit

2016

Ther Adv Med Oncol

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Lung adenocarcinoma is known for its high rate of somatic mutations and genomic rearrangements. The identification of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements that sensitize tumors to specific drugs has changed the therapeutic approach and prognosis in these molecularly-defined subgroups. Several other key genetic alterations have been identified, of which BRAF mutations are found in 4% of non-small cell lung cancer (NSCLC) cases. Targeted drugs against BRAF and downstream MEK were recently approved for the treatment of BRAF-positive melanoma and have entered clinical evaluation in NSCLC. In this review we discuss the latest evidence on the treatment of BRAF-mutated NSCLC, including tumor biology, targeted treatment with BRAF and MEK inhibitors, therapeutic resistance and strategies to overcome resistance.

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Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers

Cited by 268 publications

References 48 publications

Overcoming resistance to BRAF inhibitors

Overcoming resistance to BRAF inhibitors

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

Therapeutic approach to treating patients with BRAF-mutant lung cancer: latest evidence and clinical implications

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