Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers

(2019) Conan G. Kinsey et al.   NATURE MEDICINE

Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer

(2019) Kirsten L. Bryant et al.   NATURE MEDICINE

Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors.

(2019) Marwan Fakih et al.   JOURNAL OF CLINICAL ONCOLOGY

Design and Discovery of N-(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic

(2019) Savithri Ramurthy et al.   JOURNAL OF MEDICINAL CHEMISTRY

A patent review of BRAF inhibitors: 2013-2018

(2019) Peng-Fei Wang et al.   EXPERT OPINION ON THERAPEUTIC PATENTS

RAS mutations in human cancers: Roles in precision medicine

(2019) Avaniyapuram Kannan Murugan et al.   SEMINARS IN CANCER BIOLOGY

RAS Mutations Are Not Created Equal

(2019) G. Aaron Hobbs et al.   Cancer Discovery

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

(2019) Jiajun Yap et al.   Jove-Journal of Visualized Experiments

Cryo-EM structure of a dimeric B-Raf:14-3-3 complex reveals asymmetry in the active sites of B-Raf kinases

(2019) Yasushi Kondo et al.   SCIENCE

Architecture of autoinhibited and active BRAF–MEK1–14-3-3 complexes

(2019) Eunyoung Park et al.   NATURE

KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis

(2019) Dana Rabara et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

c-RAF Ablation Induces Regression of Advanced Kras/Trp 53 Mutant Lung Adenocarcinomas by a Mechanism Independent of MAPK Signaling

(2018) Manuel Sanclemente et al.   CANCER CELL

Oncogenic Signaling Pathways in The Cancer Genome Atlas

(2018) Francisco Sanchez-Vega et al.   CELL

An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential

(2018) Liqin Wang et al.   CELL

Forestalling BRAF-inhibitor resistance in a shocking way

(2018) Ryan J. Sullivan   CLINICAL CANCER RESEARCH

The AMPK inhibitor overcomes the paradoxical effect of RAF inhibitors through blocking the phospho-Ser-621 in the carboxyl-terminus of CRAF

(2018) Jimin Yuan et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

MEK drives BRAF activation through allosteric control of KSR proteins

(2018) Hugo Lavoie et al.   NATURE

The dynamic and stress-adaptive signaling hub of 14-3-3: emerging mechanisms of regulation and context-dependent protein–protein interactions

(2018) KL Pennington et al.   ONCOGENE

The dimer-dependent catalytic activity of RAF family kinases is revealed through characterizing their oncogenic mutants

(2018) Jimin Yuan et al.   ONCOGENE

Molecular recognition of RAS/RAF complex at the membrane: Role of RAF cysteine-rich domain

(2018) Timothy Travers et al.   Scientific Reports

Ras-Mediated Activation of the Raf Family Kinases

(2018) Elizabeth M. Terrell et al.   Cold Spring Harbor Perspectives in Medicine

RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling

(2018) Zhan Yao et al.   NATURE MEDICINE

Activating mutations in MEK1 enhance homodimerization and promote tumorigenesis

(2018) Jimin Yuan et al.   Science Signaling

PLX8394, a new generation BRAF inhibitor, selectively inhibits BRAF in colonic adenocarcinoma cells and prevents paradoxical MAPK pathway activation

(2017) Candani S. A. Tutuka et al.   Molecular Cancer

Inhibition of Isoprenylcysteine Carboxylmethyltransferase Induces Cell-Cycle Arrest and Apoptosis through p21 and p21-Regulated BNIP3 Induction in Pancreatic Cancer

(2017) Kanjoormana Aryan Manu et al.   MOLECULAR CANCER THERAPEUTICS

Current Development Status of MEK Inhibitors

(2017) et al.   MOLECULES

Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients

(2017) Ahmet Zehir et al.   NATURE MEDICINE

Combinatorial CRISPR–Cas9 screens for de novo mapping of genetic interactions

(2017) John Paul Shen et al.   NATURE METHODS

A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas

(2017) Yu Sun et al.   NEURO-ONCOLOGY

CRAF gene fusions in pediatric low-grade gliomas define a distinct drug response based on dimerization profiles

(2017) P Jain et al.   ONCOGENE

Synthetic lethality: emerging targets and opportunities in melanoma

(2017) Nicola Thompson et al.   Pigment Cell & Melanoma Research

RAF inhibitors promote RAS-RAF interaction by allosterically disrupting RAF autoinhibition

(2017) Ting Jin et al.   Nature Communications

A dynamic hydrophobic core orchestrates allostery in protein kinases

(2017) Jonggul Kim et al.   Science Advances

Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells

(2016) Zhen Li et al.   CANCER LETTERS

H-Ras and K-Ras Oncoproteins Induce Different Tumor Spectra When Driven by the Same Regulatory Sequences

(2016) Matthias Drosten et al.   CANCER RESEARCH

A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling

(2016) Sai Krishna Athuluri-Divakar et al.   CELL

B-Raf activation loop phosphorylation revisited

(2016) Martin Köhler et al.   CELL CYCLE

Therapeutic efficacy of the paradox-breaking panRAF and SRC drug CCT3833/BAL3833 in KRAS-driven cancer models

(2016) G. Saturno et al.   EUROPEAN JOURNAL OF CANCER

RAS isoforms and mutations in cancer at a glance

(2016) G. Aaron Hobbs et al.   JOURNAL OF CELL SCIENCE

Inhibition of Ras/Raf/MEK/ERK Pathway Signaling by a Stress-Induced Phospho-Regulatory Circuit

(2016) Daniel A. Ritt et al.   MOLECULAR CELL

Protein prenylation: unique fats make their mark on biology

(2016) Mei Wang et al.   NATURE REVIEWS MOLECULAR CELL BIOLOGY

Phospho-proteomic analyses of B-Raf protein complexes reveal new regulatory principles

(2016) Anja E. Eisenhardt et al.   Oncotarget

Phenotypic Characterization of a Comprehensive Set of MAPK1 /ERK2 Missense Mutants

(2016) Lisa Brenan et al.   Cell Reports

KRAS Mutant Pancreatic Cancer: No Lone Path to an Effective Treatment

(2016) Daniel Zeitouni et al.   Cancers

Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation

(2015) Pablo G. Jambrina et al.   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

Ras nanoclusters: Versatile lipid-based signaling platforms

(2015) Yong Zhou et al.   BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH

Ras activation revisited: role of GEF and GAP systems

(2015) Anne Hennig et al.   BIOLOGICAL CHEMISTRY

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

(2015) Sheng-Bin Peng et al.   CANCER CELL

BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition

(2015) Zhan Yao et al.   CANCER CELL

Activation loop phosphorylation regulates B-Raf in vivo and transformation by B-Raf mutants

(2015) M. Ko hler et al.   EMBO JOURNAL

Knock-in(g) RAF for a loop

(2015) A. Varga et al.   EMBO JOURNAL

Mechanisms of Membrane Binding of Small GTPase K-Ras4B Farnesylated Hypervariable Region

(2015) Hyunbum Jang et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Regulation of ERK Kinase by MEK1 Kinase Inhibition in the Brain

(2015) Tara C. Tassin et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Recent advances in RASopathies

(2015) Yoko Aoki et al.   JOURNAL OF HUMAN GENETICS

RAF inhibitors that evade paradoxical MAPK pathway activation

(2015) Chao Zhang et al.   NATURE

Regulation of RAF protein kinases in ERK signalling

(2015) Hugo Lavoie et al.   NATURE REVIEWS MOLECULAR CELL BIOLOGY

Allosteric Effects of the Oncogenic RasQ61L Mutant on Raf-RBD

(2015) Susan K. Fetics et al.   STRUCTURE

Discovery of RAF265: A Potent mut-B-RAF Inhibitor for the Treatment of Metastatic Melanoma

(2015) Teresa E. Williams et al.   ACS Medicinal Chemistry Letters

Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma

(2015) Sarah J. Welsh et al.   Therapeutic Advances in Medical Oncology

High prevalence of somatic MAP2K1 mutations in BRAF V600E-negative Langerhans cell histiocytosis

(2014) N. A. Brown et al.   BLOOD

An improved isoprenylcysteine carboxylmethyltransferase inhibitor induces cancer cell death and attenuates tumor growth in vivo

(2014) Hiu Yeung Lau et al.   CANCER BIOLOGY & THERAPY

Structure of the BRAF-MEK Complex Reveals a Kinase Activity Independent Role for BRAF in MAPK Signaling

(2014) Jacob R. Haling et al.   CANCER CELL

Disruption of CRAF-Mediated MEK Activation Is Required for Effective MEK Inhibition in KRAS Mutant Tumors

(2014) Piro Lito et al.   CANCER CELL

Conformational Analysis of the DFG-Out Kinase Motif and Biochemical Profiling of Structurally Validated Type II Inhibitors

(2014) R. S. K. Vijayan et al.   JOURNAL OF MEDICINAL CHEMISTRY

Kinase Regulation by Hydrophobic Spine Assembly in Cancer

(2014) Jiancheng Hu et al.   MOLECULAR AND CELLULAR BIOLOGY

Kinases and Pseudokinases: Lessons from RAF

(2014) A. S. Shaw et al.   MOLECULAR AND CELLULAR BIOLOGY

Inhibition of HSP90 by AT13387 Delays the Emergence of Resistance to BRAF Inhibitors and Overcomes Resistance to Dual BRAF and MEK Inhibition in Melanoma Models

(2014) T. Smyth et al.   MOLECULAR CANCER THERAPEUTICS

Protein interaction switches coordinate Raf-1 and MST2/Hippo signalling

(2014) David Romano et al.   NATURE CELL BIOLOGY

Drugging the undruggable RAS: Mission Possible?

(2014) Adrienne D. Cox et al.   NATURE REVIEWS DRUG DISCOVERY

Crystal structure of a BRAF kinase domain monomer explains basis for allosteric regulation

(2014) Neroshan Thevakumaran et al.   NATURE STRUCTURAL & MOLECULAR BIOLOGY

Isoprenylcysteine carboxylmethyltransferase regulates mitochondrial respiration and cancer cell metabolism

(2014) J T Teh et al.   ONCOGENE

The landscape of kinase fusions in cancer

(2014) Nicolas Stransky et al.   Nature Communications

Pseudokinases from a structural perspective

(2013) Susan S. Taylor et al.   BIOCHEMICAL SOCIETY TRANSACTIONS

A New Mode of RAF Autoregulation: A Further Complication in the Inhibitor Paradox

(2013) Fiona Hey et al.   CANCER CELL

RAF Inhibitors Activate the MAPK Pathway by Relieving Inhibitory Autophosphorylation

(2013) Matthew Holderfield et al.   CANCER CELL

Allosteric Activation of Functionally Asymmetric RAF Kinase Dimers

(2013) Jiancheng Hu et al.   CELL

A new signaling paradigm to control the prenylation and trafficking of small GTPases

(2013) Carol Williams   CELL CYCLE

Ins and Outs of Kinase DFG Motifs

(2013) Daniel K. Treiber et al.   CHEMISTRY & BIOLOGY

Discovery of a Selective Kinase Inhibitor (TAK-632) Targeting Pan-RAF Inhibition: Design, Synthesis, and Biological Evaluation of C-7-Substituted 1,3-Benzothiazole Derivatives

(2013) Masanori Okaniwa et al.   JOURNAL OF MEDICINAL CHEMISTRY

K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions

(2013) Jonathan M. Ostrem et al.   NATURE

RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation

(2012) Madhurima Saha et al.   BIOCHEMICAL JOURNAL

Ras inhibition via direct Ras binding—is there a path forward?

(2012) Weiru Wang et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

How to Fool a Wonder Drug: Truncate and Dimerize

(2012) Miriam Molina-Arcas et al.   CANCER CELL

Calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylates Raf-1 at serine 338 and mediates Ras-stimulated Raf-1 activation

(2012) Marcella Salzano et al.   CELL CYCLE

The HSP90 Inhibitor XL888 Overcomes BRAF Inhibitor Resistance Mediated through Diverse Mechanisms

(2012) K. H. T. Paraiso et al.   CLINICAL CANCER RESEARCH

Distinct requirement for an intact dimer interface in wild-type, V600E and kinase-dead B-Raf signalling

(2012) Michael Röring et al.   EMBO JOURNAL

The intermediate-activity L597VBRAF mutant acts as an epistatic modifier of oncogenic RAS by enhancing signaling through the RAF/MEK/ERK pathway

(2012) C. Andreadi et al.   GENES & DEVELOPMENT

Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial

(2012) Axel Hauschild et al.   LANCET

Successful rechallenge in two patients with BRAF-V600-mutant melanoma who experienced previous progression during treatment with a selective BRAF inhibitor

(2012) Amélie Clémentine Seghers et al.   MELANOMA RESEARCH

An integrated encyclopedia of DNA elements in the human genome

(2012)   NATURE

Elucidating Distinct Roles for NF1 in Melanomagenesis

(2012) Ophélia Maertens et al.   Cancer Discovery

BRAF L597 Mutations in Melanoma Are Associated with Sensitivity to MEK Inhibitors

(2012) Kimberly Brown Dahlman et al.   Cancer Discovery

DUSPs, to MAP kinases and beyond

(2012) Ching-Yu Huang et al.   Cell and Bioscience

Oncogenic FAM131B–BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma

(2011) Huriye Cin et al.   ACTA NEUROPATHOLOGICA

c-Raf, but Not B-Raf, Is Essential for Development of K-Ras Oncogene-Driven Non-Small Cell Lung Carcinoma

(2011) Rafael B. Blasco et al.   CANCER CELL

Single Substitution within the RKTR Motif Impairs Kinase Activity but Promotes Dimerization of RAF Kinase

(2011) Angela Baljuls et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK

(2011) Damian F. Brennan et al.   NATURE

RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)

(2011) Poulikos I. Poulikakos et al.   NATURE

Regulating the regulator: post-translational modification of RAS

(2011) Ian M. Ahearn et al.   NATURE REVIEWS MOLECULAR CELL BIOLOGY

Mutation that blocks ATP binding creates a pseudokinase stabilizing the scaffolding function of kinase suppressor of Ras, CRAF and BRAF

(2011) J. Hu et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

14-3-3 Proteins: Diverse functions in cell proliferation and cancer progression

(2011) Alyson K. Freeman et al.   SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY

S-Farnesyl-Thiopropionic Acid Triazoles as Potent Inhibitors of Isoprenylcysteine Carboxyl Methyltransferase

(2011) Joel A. Bergman et al.   ACS Medicinal Chemistry Letters

C-Raf Is Required for the Initiation of Lung Cancer by K-Ras G12D

(2011) Florian A. Karreth et al.   Cancer Discovery

BRAF, a target in melanoma

(2010) Keith T. Flaherty et al.   CANCER

Heterogeneous Nuclear Ribonucleoprotein H Blocks MST2-Mediated Apoptosis in Cancer Cells by Regulating a-raf Transcription

(2010) J. Rauch et al.   CANCER RESEARCH

Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells

(2010) Zhenfeng Zhang et al.   CARCINOGENESIS

The Brothers RAF

(2010) Lawrence N. Kwong et al.   CELL

Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF

(2010) Sonja J. Heidorn et al.   CELL

Impaired Binding of 14-3-3 to C-RAF in Noonan Syndrome Suggests New Approaches in Diseases with Increased Ras Signaling

(2010) M. Molzan et al.   MOLECULAR AND CELLULAR BIOLOGY

Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma

(2010) Nallasivam Palanisamy et al.   NATURE MEDICINE

COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer

(2010) S. A. Forbes et al.   NUCLEIC ACIDS RESEARCH

Inhibition of isoprenylcysteine carboxylmethyltransferase induces autophagic-dependent apoptosis and impairs tumor growth

(2010) M Wang et al.   ONCOGENE

Protein kinases: evolution of dynamic regulatory proteins

(2010) Susan S. Taylor et al.   TRENDS IN BIOCHEMICAL SCIENCES

Raf-1 Addiction in Ras-Induced Skin Carcinogenesis

(2009) Karin Ehrenreiter et al.   CANCER CELL

The C-terminus of Raf-1 acts as a 14-3-3-dependent activation switch

(2009) Amardeep S. Dhillon et al.   CELLULAR SIGNALLING

Drosophila Raf's N Terminus Contains a Novel Conserved Region and Can Contribute to Torso RTK Signaling

(2009) J. Ding et al.   GENETICS

GermlineBRAFmutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: Molecular diversity and associated phenotypic spectrum

(2009) Anna Sarkozy et al.   HUMAN MUTATION

From autoinhibition to inhibition in trans: the Raf-1 regulatory domain inhibits Rok-α kinase activity

(2009) Théodora Niault et al.   JOURNAL OF CELL BIOLOGY

Impact of Feedback Phosphorylation and Raf Heterodimerization on Normal and Mutant B-Raf Signaling

(2009) D. A. Ritt et al.   MOLECULAR AND CELLULAR BIOLOGY

A dimerization-dependent mechanism drives RAF catalytic activation

(2009) Thanashan Rajakulendran et al.   NATURE

Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within theDUSP6/MKP-3gene promoter

(2008) Maria Ekerot et al.   BIOCHEMICAL JOURNAL

Fluoride complexes of oncogenic Ras mutants to study the Ras-RasGAP interaction

(2008) Lothar Gremer et al.   BIOLOGICAL CHEMISTRY

Inactivating Icmt ameliorates K-RAS-induced myeloproliferative disease

(2008) A. M. Wahlstrom et al.   BLOOD

Tandem Duplication Producing a Novel OncogenicBRAFFusion Gene Defines the Majority of Pilocytic Astrocytomas

(2008) David T.W. Jones et al.   CANCER RESEARCH

Positive Regulation of A-RAF by Phosphorylation of Isoform-specific Hinge Segment and Identification of Novel Phosphorylation Sites

(2008) Angela Baljuls et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

A Small Molecule Inhibitor of Isoprenylcysteine Carboxymethyltransferase Induces Autophagic Cell Death in PC3 Prostate Cancer Cells

(2008) Mei Wang et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

p21 activated kinase 5 activates Raf-1 and targets it to mitochondria

(2008) Xiaochong Wu et al.   JOURNAL OF CELLULAR BIOCHEMISTRY

The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth

(2008) Heather R. Christofk et al.   NATURE

Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon

(2008) Kevin M Haigis et al.   NATURE GENETICS

CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations

(2008) K S M Smalley et al.   ONCOGENE

Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity

(2008) J. Tsai et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA