Relief of Feedback Inhibition of <i>HER3</i> Transcription by RAF and MEK Inhibitors Attenuates Their Antitumor Effects in <i>BRAF</i>-Mutant Thyroid Carcinomas

Montero‐Conde, Cristina; Ruiz‐Llorente, Sergio; Domínguez, José Miguel; Knauf, Jeffrey A.; Viale, Agnès; Sherman, Eric J.; Ryder, Mabel; Ghossein, Ronald; Rosen, Neal; Fagin, James A.

doi:10.1158/2159-8290.cd-12-0531

Cited by 347 publications

(378 citation statements)

References 40 publications

(50 reference statements)

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“…SKMEL208 cells were provided by Taha Merghoub and David Solit (MSKCC). Thyroid tumor cell lines 8505C, Hth104 and SW1736 have been authenticated as previously reported (Montero-Conde et al, 2013). All other cell lines were from ATCC.…”

Section: Methodsmentioning

confidence: 99%

“…Colorectal and thyroid BRAF V600E tumors are resistant to first generation RAF inhibitors (Corcoran et al, 2012;Montero-Conde et al, 2013;Prahallad et al, 2012). To assess whether RAF dimerization contributes to drug resistance in these tumors, we first compared the levels of BRAF/CRAF dimerization between melanoma and colorectal or thyroid BRAF V600E cells lines.…”

Section: αC-in Inhibitors Show Increased Activity In Colorectal and Tmentioning

confidence: 99%

“…Furthermore, preclinical and clinical evidence suggests that these RAF inhibitors will not be effective in colorectal and thyroid BRAF V600E tumors due to relief of negative feedback and RTK-mediated reactivation of ERK signaling (Corcoran et al, 2012;Montero-Conde et al, 2013;Prahallad et al, 2012). Thus, there is pressing need for the development of more effective inhibitor-based therapeutic strategies to target BRAF oncogenic signaling in various clinical contexts.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

Section: αC-in Inhibitors Show Increased Activity In Colorectal and Tmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Karoulia¹,

Wu²,

Ahmed³

et al. 2016

Cancer Cell

127

View full text Add to dashboard Cite

show abstract

“…The clinical success and approval of the BRAF inhibitors vemurafenib and dabrafenib in BRAF V600E melanoma have provided a rationale for testing BRAF inhibition in nonmelanoma patients whose tumors harbor BRAF mutations (8)(9)(10). The success of such efforts has been limited, with either BRAF-inhibitor treatment or downstream MAPK blockade failing to produce the desired clinical activity in patients with colorectal and thyroid cancers harboring BRAF V600E ; in both cases the failure is caused by intrinsic resistance (11)(12)(13). These observations indicate that tumor cell oncogene dependence is context specific and underscore the need to define the molecular events that regulate oncogene dependence in each tumor type to optimize clinical responses.…”

mentioning

confidence: 99%

Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer

Asthana

Chan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Oncogenic mutations in the BRAF kinase occur in 6-8% of nonsmall cell lung cancers (NSCLCs), accounting for more than 90,000 deaths annually worldwide. The biological and clinical relevance of these BRAF mutations in NSCLC is incompletely understood. Here we demonstrate that human NSCLC cells with BRAF V600E , but not other BRAF mutations, initially are sensitive to BRAF-inhibitor treatment. However, these BRAF V600E NSCLC cells rapidly acquire resistance to BRAF inhibition through at least one of two discrete molecular mechanisms: (i) loss of full-length BRAF V600E coupled with expression of an aberrant form of BRAF V600E that retains RAF pathway dependence or (ii) constitutive autocrine EGF receptor (EGFR) signaling driven by c-Jun-mediated EGFR ligand expression. BRAF V600E cells with EGFR-driven resistance are characterized by hyperphosphorylated protein kinase AKT, a biomarker we validated in BRAF inhibitor-resistant NSCLC clinical specimens. These data reveal the multifaceted molecular mechanisms by which NSCLCs establish and regulate BRAF oncogene dependence, provide insights into BRAF-EGFR signaling crosstalk, and uncover mechanism-based strategies to optimize clinical responses to BRAF oncogene inhibition.targeted therapy | combination therapy

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“…This autocrine loop led to ERK and AKT overactivation that contributed to attenuate the antitumor effect of BRAF inhibitor, which was restored by combination with the selective HER inhibitor lapatinib [20]. thereby implying an enhanced therapeutic efficacy.…”

Section: Resistance To Braf Inhibitorsmentioning

confidence: 99%

Resistance to Kinase Inhibitors in Poorly Differentiated and Anaplastic Thyroid Cancer: Preclinical In vitro Evidences

F¹,

Tumino²,

Frasca³

2016

Endocrinol Metab Syndr

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Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are rare but highly aggressive malignancies with an extremely short survival. Poor prognosis is due to their unlimited growth, invasion, migration and resistance to common anticancer therapies. Advances in understanding the molecular alterations in thyroid carcinomas led to development of new therapeutic strategies such as kinase inhibitors. Although several of these compounds have been approved by FDA and EMA for the treatment of radioactive-iodine refractory differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC), no significant clinical efficacy with targeted therapies have been observed in those patients.Herein, we review and summarize the preclinical in vitro evidences of mechanisms of resistance to kinase inhibitors currently used in PDTC and ATC patients.

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Relief of Feedback Inhibition of HER3 Transcription by RAF and MEK Inhibitors Attenuates Their Antitumor Effects in BRAF-Mutant Thyroid Carcinomas

Cited by 347 publications

References 40 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

Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer

Resistance to Kinase Inhibitors in Poorly Differentiated and Anaplastic Thyroid Cancer: Preclinical In vitro Evidences

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