Targeting RAS–ERK signalling in cancer: promises and challenges

Somatic activating ARAF mutations in Langerhans cell histiocytosis

(2014) D. S. Nelson et al.   BLOOD

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

(2014) Piro Lito et al.   CANCER CELL

Loss of NF1 in Cutaneous Melanoma Is Associated with RAS Activation and MEK Dependence

(2014) Moriah H. Nissan et al.   CANCER RESEARCH

Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma

(2014) Marcin Imielinski et al.   JOURNAL OF CLINICAL INVESTIGATION

Differential activity of MEK and ERK inhibitors in BRAF inhibitor resistant melanoma

(2014) Matteo S. Carlino et al.   Molecular Oncology

Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma

(2014) Chong Sun et al.   NATURE

A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics

(2014) Apirat Chaikuad et al.   Nature Chemical Biology

Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors

(2014) Kevin J. Basile et al.   Pigment Cell & Melanoma Research

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

(2014) L. Lin et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange

(2014) Michael C. Burns et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Mixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors

(2014) Anna A. Marusiak et al.   Nature Communications

Efficacy of Intermittent Combined RAF and MEK Inhibition in a Patient with Concurrent BRAF- and NRAS-Mutant Malignancies

(2014) O. Abdel-Wahab et al.   Cancer Discovery

RAF Inhibitors Activate the MAPK Pathway by Relieving Inhibitory Autophosphorylation

(2013) Matthew Holderfield et al.   CANCER CELL

Antitumor Activity of the Selective Pan-RAF Inhibitor TAK-632 in BRAF Inhibitor-Resistant Melanoma

(2013) A. Nakamura et al.   CANCER RESEARCH

Enhanced Inhibition of ERK Signaling by a Novel Allosteric MEK Inhibitor, CH5126766, That Suppresses Feedback Reactivation of RAF Activity

(2013) Nobuya Ishii et al.   CANCER RESEARCH

Allosteric Activation of Functionally Asymmetric RAF Kinase Dimers

(2013) Jiancheng Hu et al.   CELL

A phase 1b study of trametinib, an oral Mitogen-activated protein kinase kinase (MEK) inhibitor, in combination with gemcitabine in advanced solid tumours

(2013) Jeffrey R. Infante et al.   EUROPEAN JOURNAL OF CANCER

Resistance to BRAF-targeted therapy in melanoma

(2013) Ryan J. Sullivan et al.   EUROPEAN JOURNAL OF CANCER

MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study

(2013) Paolo A Ascierto et al.   LANCET ONCOLOGY

Antiproliferative Effects of Continued Mitogen-Activated Protein Kinase Pathway Inhibition following Acquired Resistance to BRAF and/or MEK Inhibition in Melanoma

(2013) M. S. Carlino et al.   MOLECULAR CANCER THERAPEUTICS

Effects of Raf Dimerization and Its Inhibition on Normal and Disease-Associated Raf Signaling

(2013) Alyson K. Freeman et al.   MOLECULAR CELL

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

(2013) Jonathan M. Ostrem et al.   NATURE

Small molecule inhibition of the KRAS–PDEδ interaction impairs oncogenic KRAS signalling

(2013) Gunther Zimmermann et al.   NATURE

Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers

(2013) Georgia Hatzivassiliou et al.   NATURE

Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance

(2013) Meghna Das Thakur et al.   NATURE

Inhibitors that stabilize a closed RAF kinase domain conformation induce dimerization

(2013) Hugo Lavoie et al.   Nature Chemical Biology

Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas

(2013) A. J. Sievert et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction

(2013) F. Shima et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

A Genome-Scale RNA Interference Screen Implicates NF1 Loss in Resistance to RAF Inhibition

(2013) Steven R. Whittaker et al.   Cancer Discovery

Acquired Resistance and Clonal Evolution in Melanoma during BRAF Inhibitor Therapy

(2013) H. Shi et al.   Cancer Discovery

MAP Kinase Pathway Alterations in BRAF-Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition

(2013) N. Wagle et al.   Cancer Discovery

Discovery of a Novel ERK Inhibitor with Activity in Models of Acquired Resistance to BRAF and MEK Inhibitors

(2013) E. J. Morris et al.   Cancer Discovery

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

(2013) Cristina Montero-Conde et al.   Cancer Discovery

Discovery of Small Molecules that Bind to K-Ras and Inhibit Sos-Mediated Activation

(2012) Qi Sun et al.   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation

(2012) J. Haroche et al.   BLOOD

High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses

(2012) J. Haroche et al.   BLOOD

Relief of Profound Feedback Inhibition of Mitogenic Signaling by RAF Inhibitors Attenuates Their Activity in BRAFV600E Melanomas

(2012) Piro Lito et al.   CANCER CELL

Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of the MEK Inhibitor RO4987655 (CH4987655) in Patients with Advanced Solid Tumors

(2012) S. Leijen et al.   CLINICAL CANCER RESEARCH

First-in-Human, Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of RO5126766, a First-in-Class Dual MEK/RAF Inhibitor in Patients with Solid Tumors

(2012) M. Martinez-Garcia 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

Phase II Study of the MEK1/MEK2 Inhibitor Trametinib in Patients With MetastaticBRAF-Mutant Cutaneous Melanoma Previously Treated With or Without a BRAF Inhibitor

(2012) Kevin B. Kim et al.   JOURNAL OF CLINICAL ONCOLOGY

Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial

(2012) Gerald S Falchook et al.   LANCET

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

(2012) Axel Hauschild et al.   LANCET

Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial

(2012) Gerald S Falchook et al.   LANCET ONCOLOGY

Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study

(2012) Pasi A Jänne et al.   LANCET ONCOLOGY

Increased BRAF Heterodimerization Is the Common Pathogenic Mechanism for Noonan Syndrome-Associated RAF1 Mutants

(2012) X. Wu et al.   MOLECULAR AND CELLULAR BIOLOGY

ERK Inhibition Overcomes Acquired Resistance to MEK Inhibitors

(2012) G. Hatzivassiliou et al.   MOLECULAR CANCER THERAPEUTICS

Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR

(2012) Anirudh Prahallad et al.   NATURE

Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion

(2012) Ravid Straussman et al.   NATURE

Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors

(2012) Timothy R. Wilson et al.   NATURE

Progression of RAS-Mutant Leukemia during RAF Inhibitor Treatment

(2012) Margaret K. Callahan et al.   NEW ENGLAND JOURNAL OF MEDICINE

Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations

(2012) Keith T. Flaherty et al.   NEW ENGLAND JOURNAL OF MEDICINE

Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma

(2012) Keith T. Flaherty et al.   NEW ENGLAND JOURNAL OF MEDICINE

RASMutations in Cutaneous Squamous-Cell Carcinomas in Patients Treated with BRAF Inhibitors

(2012) Fei Su et al.   NEW ENGLAND JOURNAL OF MEDICINE

Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity

(2012) T. Maurer et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Melanoma whole-exome sequencing identifies V600E B-RAF amplification-mediated acquired B-RAF inhibitor resistance

(2012) Hubing Shi et al.   Nature Communications

EGFR-Mediated Reactivation of MAPK Signaling Contributes to Insensitivity of BRAF -Mutant Colorectal Cancers to RAF Inhibition with Vemurafenib

(2012) Ryan B. Corcoran et al.   Cancer Discovery

Inhibiting EGF Receptor or SRC Family Kinase Signaling Overcomes BRAF Inhibitor Resistance in Melanoma

(2012) Maria R. Girotti et al.   Cancer Discovery

Elucidating Distinct Roles for NF1 in Melanomagenesis

(2012) Ophélia Maertens et al.   Cancer Discovery

Oncogenic and Wild-type Ras Play Divergent Roles in the Regulation of Mitogen-Activated Protein Kinase Signaling

(2012) Amy Young et al.   Cancer Discovery

MEK1/2 dual-specificity protein kinases: Structure and regulation

(2011) Robert Roskoski   BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

Discovery of TAK-733, a potent and selective MEK allosteric site inhibitor for the treatment of cancer

(2011) Qing Dong et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Mutant BRAF Melanomas—Dependence and Resistance

(2011) Poulikos I. Poulikakos et al.   CANCER CELL

A phase I, open-label, randomized crossover study to assess the effect of dosing of the MEK 1/2 inhibitor Selumetinib (AZD6244; ARRY-142866) in the presence and absence of food in patients with advanced solid tumors

(2011) Suzanne Leijen et al.   CANCER CHEMOTHERAPY AND PHARMACOLOGY

MEK1 mutations, but not ERK2 mutations, occur in melanomas and colon carcinomas, but none in thyroid carcinomas

(2011) Avaniyapuram Kannan Murugan et al.   CELL CYCLE

Phase II, Open-Label, Randomized Trial of the MEK1/2 Inhibitor Selumetinib as Monotherapy versus Temozolomide in Patients with Advanced Melanoma

(2011) J. M. Kirkwood et al.   CLINICAL CANCER RESEARCH

GSK1120212 (JTP-74057) Is an Inhibitor of MEK Activity and Activation with Favorable Pharmacokinetic Properties for Sustained In Vivo Pathway Inhibition

(2011) A. G. Gilmartin et al.   CLINICAL CANCER RESEARCH

Inhibition of Ras for cancer treatment: the search continues

(2011) Antonio T Baines et al.   Future Medicinal Chemistry

BRAFV600E: Implications for Carcinogenesis and Molecular Therapy

(2011) E. R. Cantwell-Dorris et al.   MOLECULAR CANCER THERAPEUTICS

Strong negative feedback from Erk to Raf confers robustness to MAPK signalling

(2011) R. Fritsche-Guenther et al.   Molecular Systems Biology

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

(2011) Poulikos I. Poulikakos et al.   NATURE

Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation

(2011) Paul B. Chapman et al.   NEW ENGLAND JOURNAL OF MEDICINE

Recurrent BRAF mutations in Langerhans cell histiocytosis

(2010) G. Badalian-Very et al.   BLOOD

Blockade of the MEK/ERK signalling cascade by AS703026, a novel selective MEK1/2 inhibitor, induces pleiotropic anti-myeloma activity in vitro and in vivo

(2010) Kihyun Kim et al.   BRITISH JOURNAL OF HAEMATOLOGY

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

(2010) Jessie Villanueva et al.   CANCER CELL

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

(2010) Sonja J. Heidorn et al.   CELL

A Phase II Study of PD-0325901, an Oral MEK Inhibitor, in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer

(2010) E. B. Haura et al.   CLINICAL CANCER RESEARCH

Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral MAPK/ERK Kinase Inhibitor PD-0325901 in Patients with Advanced Cancers

(2010) P. M. LoRusso et al.   CLINICAL CANCER RESEARCH

The First-in-Human Study of the Hydrogen Sulfate (Hyd-Sulfate) Capsule of the MEK1/2 Inhibitor AZD6244 (ARRY-142886): A Phase I Open-Label Multicenter Trial in Patients with Advanced Cancer

(2010) U. Banerji et al.   CLINICAL CANCER RESEARCH

RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF

(2010) Poulikos I. Poulikakos et al.   NATURE

RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth

(2010) Georgia Hatzivassiliou et al.   NATURE

Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma

(2010) Gideon Bollag et al.   NATURE

COT drives resistance to RAF inhibition through MAP kinase pathway reactivation

(2010) Cory M. Johannessen et al.   NATURE

Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation

(2010) Ramin Nazarian et al.   NATURE

Inhibition of Mutated, Activated BRAF in Metastatic Melanoma

(2010) Keith T. Flaherty et al.   NEW ENGLAND JOURNAL OF MEDICINE

Meenhard Herlyn

(2010) Ruth Halaban   Pigment Cell & Melanoma Research

The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner

(2010) E. W. Joseph et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Targeting the RAF–MEK–ERK pathway in cancer therapy

(2009) Clara Montagut et al.   CANCER LETTERS

RDEA119/BAY 869766: A Potent, Selective, Allosteric Inhibitor of MEK1/2 for the Treatment of Cancer

(2009) C. Iverson et al.   CANCER RESEARCH

Structure-Guided Design of Potent and Selective Pyrimidylpyrrole Inhibitors of Extracellular Signal-Regulated Kinase (ERK) Using Conformational Control

(2009) Alex M. Aronov et al.   JOURNAL OF MEDICINAL CHEMISTRY

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

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

C-Raf Inhibits MAPK Activation and Transformation by B-RafV600E

(2009) Florian A. Karreth et al.   MOLECULAR CELL

A dimerization-dependent mechanism drives RAF catalytic activation

(2009) Thanashan Rajakulendran et al.   NATURE

MEK1 mutations confer resistance to MEK and B-RAF inhibition

(2009) C. M. Emery et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Novel MEK1 Mutation Identified by Mutational Analysis of Epidermal Growth Factor Receptor Signaling Pathway Genes in Lung Adenocarcinoma

(2008) J. L. Marks et al.   CANCER RESEARCH

Elevated CRAF as a Potential Mechanism of Acquired Resistance to BRAF Inhibition in Melanoma

(2008) C. Montagut et al.   CANCER RESEARCH

Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced Cancers

(2008) Alex A. Adjei et al.   JOURNAL OF CLINICAL ONCOLOGY

Targeting RAS and PI3K in lung cancer

(2008) Julian Downward   NATURE MEDICINE

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