Drugging the Undruggable: Advances on RAS Targeting in Cancer

MO01.32 CodeBreaK 200: A Phase 3 Multicenter Study of Sotorasib, a KRAS(G12C) Inhibitor, versus Docetaxel in Patients with Previously Treated Advanced Non-Small Cell Lung Cancer (NSCLC) Harboring KRAS p.G12C Mutation

(2021) M. Reck et al.   Journal of Thoracic Oncology

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

(2021) Hyuna Sung et al.   CA-A CANCER JOURNAL FOR CLINICIANS

RAF1 kinase activity is dispensable for KRAS/p53 mutant lung tumor progression

(2021) Manuel Sanclemente et al.   CANCER CELL

Cell-type Specific Adaptive Signaling Responses to KRASG12C inhibition

(2021) Eric B Haura et al.   CLINICAL CANCER RESEARCH

NRAS is unique among RAS proteins in requiring ICMT for trafficking to the plasma membrane

(2021) Ian M Ahearn et al.   Life Science Alliance

PS01.07 Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutant NSCLC: First Disclosure of the Codebreak 100 Primary Analysis

(2021) B. Li et al.   Journal of Thoracic Oncology

99O_PR KRYSTAL-1: Activity and preliminary pharmacodynamic (PD) analysis of adagrasib (MRTX849) in patients (Pts) with advanced non–small cell lung cancer (NSCLC) harboring KRASG12C mutation

(2021) G.J. Riely et al.   Journal of Thoracic Oncology

The KRASG12C Inhibitor MRTX849 Reconditions the Tumor Immune Microenvironment and Sensitizes Tumors to Checkpoint Inhibitor Therapy

(2021) David M. Briere et al.   MOLECULAR CANCER THERAPEUTICS

Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation

(2021) Noritaka Tanaka et al.   Cancer Discovery

Allosteric SHP2 inhibitors in cancer: Targeting the intersection of RAS, resistance, and the immune microenvironment

(2021) D. Lucas Kerr et al.   CURRENT OPINION IN CHEMICAL BIOLOGY

Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future

(2020) Laura M Spring et al.   LANCET

Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition

(2020) Jenny Y. Xue et al.   NATURE

Current Advances in the Treatment of BRAF-Mutant Melanoma

(2020) Hima Patel et al.   Cancers

The Frequency of Ras Mutations in Cancer

(2020) Ian A. Prior et al.   CANCER RESEARCH

A phase II study of siG12D-LODER in combination with chemotherapy in patients with locally advanced pancreatic cancer (PROTACT).

(2020) Anna M. Varghese et al.   JOURNAL OF CLINICAL ONCOLOGY

Selumetinib in Children with Inoperable Plexiform Neurofibromas

(2020) Andrea M. Gross et al.   NEW ENGLAND JOURNAL OF MEDICINE

RAF kinase dimerization: implications for drug discovery and clinical outcomes

(2020) Tilman Brummer et al.   ONCOGENE

EGFR blockade reverts resistance to KRAS G12C inhibition in colorectal cancer

(2020) Vito Amodio et al.   Cancer Discovery

Repression of the Type I Interferon Pathway Underlies MYC- and KRAS-Dependent Evasion of NK and B Cells in Pancreatic Ductal Adenocarcinoma

(2020) Nathiya Muthalagu et al.   Cancer Discovery

Defining and Targeting Adaptations to Oncogenic KRASG12C Inhibition Using Quantitative Temporal Proteomics

(2020) Naiara Santana-Codina et al.   Cell Reports

RAS-targeted therapies: is the undruggable drugged?

(2020) Amanda R. Moore et al.   NATURE REVIEWS DRUG DISCOVERY

Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers

(2020) Irem Ozkan-Dagliyan et al.   Cell Reports

Epithelial-to-Mesenchymal Transition is a Cause of Both Intrinsic and Acquired Resistance to KRAS G12C Inhibitor in KRAS G12C–Mutant Non–Small Cell Lung Cancer

(2020) Yuta Adachi et al.   CLINICAL CANCER RESEARCH

Targeting a KRAS neoantigen peptide vaccine to DNGR-1+ dendritic cells

(2020) R. Ambler et al.   EUROPEAN JOURNAL OF CANCER

SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling

(2020) Carmine Fedele et al.   JOURNAL OF EXPERIMENTAL MEDICINE

Structural basis for the action of the drug trametinib at KSR-bound MEK

(2020) Zaigham M. Khan et al.   NATURE

KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors

(2020) David S. Hong et al.   NEW ENGLAND JOURNAL OF MEDICINE

BI-3406, a potent and selective SOS1::KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition

(2020) Marco H Hofmann et al.   Cancer Discovery

GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf

(2020) Ziyang Zhang et al.   ACS Central Science

Treatment of Advanced Melanoma: Past, Present and Future

(2020) Taku Fujimura et al.   Life-Basel

Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS–SOS1 interaction

(2019) Roman C. Hillig et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

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

KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer

(2019) Wenting Liao et al.   CANCER CELL

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

A phase I/II multiple expansion cohort trial of MRTX849 in patients with advanced solid tumors with KRAS G12C mutation.

(2019) Kyriakos P. Papadopoulos et al.   JOURNAL OF CLINICAL ONCOLOGY

K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways

(2019) Matthias Scheffler et al.   Journal of Thoracic Oncology

KRASG12C inhibition produces a driver-limited state revealing collateral dependencies

(2019) Kevin Lou et al.   Science Signaling

Endogenous CD4+ T Cells Recognize Neoantigens in Lung Cancer Patients, Including Recurrent Oncogenic KRAS and ERBB2 (Her2) Driver Mutations

(2019) Joshua R. Veatch et al.   Cancer Immunology Research

Five-Year Overall Survival for Patients With Advanced Non‒Small-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study

(2019) Edward B. Garon et al.   JOURNAL OF CLINICAL ONCOLOGY

A Potent Isoprenylcysteine Carboxylmethyltransferase (ICMT) Inhibitor Improves Survival in Ras-Driven Acute Myeloid Leukemia

(2019) Nagore I. Marín-Ramos et al.   JOURNAL OF MEDICINAL CHEMISTRY

Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma

(2019) Caroline Robert et al.   NEW ENGLAND JOURNAL OF MEDICINE

Coxsackievirus Type B3 is A Potent Oncolytic Virus against KRAS-Mutant Lung Adenocarcinoma

(2019) Haoyu Deng et al.   Molecular Therapy-Oncolytics

Phase Ib Study of Combination Therapy with MEK Inhibitor Binimetinib and Phosphatidylinositol 3‐Kinase Inhibitor Buparlisib in Patients with Advanced Solid Tumors with RAS/RAF Alterations

(2019) Aditya Bardia et al.   ONCOLOGIST

Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer

(2019) Miriam Molina-Arcas et al.   Science Translational Medicine

Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition

(2019) Meagan B. Ryan et al.   CLINICAL CANCER RESEARCH

OA02.02 Phase 1 Study of Safety, Tolerability, PK and Efficacy of AMG 510, a Novel KRASG12C Inhibitor, Evaluated in NSCLC

(2019) R. Govindan et al.   Journal of Thoracic Oncology

The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity

(2019) Jude Canon et al.   NATURE

The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients

(2019) Jill Hallin et al.   Cancer Discovery

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

Comprehensive Characterization of Cancer Driver Genes and Mutations

(2018) Matthew H. Bailey et al.   CELL

Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor

(2018) Matthew R. Janes et al.   CELL

Back to the Bench? MEK and ERK Inhibitors for the Treatment of KRAS Mutant Lung Adenocarcinoma

(2018) Jens Kohler et al.   CURRENT MEDICINAL CHEMISTRY

Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase

(2018) Dietrich A. Ruess et al.   NATURE MEDICINE

STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS -Mutant Lung Adenocarcinoma

(2018) Ferdinandos Skoulidis et al.   Cancer Discovery

OUP accepted manuscript

(2018)   ANNALS OF ONCOLOGY

RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers

(2018) Robert J. Nichols et al.   NATURE CELL BIOLOGY

SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models

(2018) Carmine Fedele et al.   Cancer Discovery

Pharmacological Induction of RAS-GTP Confers RAF Inhibitor Sensitivity in KRAS Mutant Tumors

(2018) Ivana Yen et al.   CANCER CELL

KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition

(2018) Sandra Misale et al.   CLINICAL CANCER RESEARCH

Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA

(2017) Matthew A. Coelho et al.   IMMUNITY

Selumetinib Plus Docetaxel Compared With Docetaxel Alone and Progression-Free Survival in Patients With KRAS-Mutant Advanced Non–Small Cell Lung Cancer

(2017) Pasi A. Jänne et al.   JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION

Oncogenic KRAS-associated gene signature defines co-targeting of CDK4/6 and MEK as a viable therapeutic strategy in colorectal cancer

(2017) M Pek et al.   ONCOGENE

Survival of pancreatic cancer cells lacking KRAS function

(2017) Mandar Deepak Muzumdar et al.   Nature Communications

Kras and Tumor Immunity: Friend or Foe?

(2017) Jane Cullis et al.   Cold Spring Harbor Perspectives in Medicine

Combined MEK and ERK inhibition overcomes therapy-mediated pathway reactivation in RAS mutant tumors

(2017) Mark Merchant et al.   PLoS One

8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells

(2016) Idrees Mohammed et al.   BIOORGANIC & MEDICINAL CHEMISTRY

RAS isoforms and mutations in cancer at a glance

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

Randomized Phase 2 Trial of the Oncolytic Virus Pelareorep (Reolysin) in Upfront Treatment of Metastatic Pancreatic Adenocarcinoma

(2016) Anne M Noonan et al.   MOLECULAR THERAPY

A combinatorial strategy for treating KRAS-mutant lung cancer

(2016) Eusebio Manchado et al.   NATURE

T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer

(2016) Eric Tran et al.   NEW ENGLAND JOURNAL OF MEDICINE

Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism

(2016) P. Lito et al.   SCIENCE

Epithelial-to-Mesenchymal Transition Defines Feedback Activation of Receptor Tyrosine Kinase Signaling Induced by MEK Inhibition in KRAS-Mutant Lung Cancer

(2016) H. Kitai et al.   Cancer Discovery

Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State

(2016) M. P. Patricelli et al.   Cancer Discovery

A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)†

(2015) G. R. Blumenschein et al.   ANNALS OF ONCOLOGY

Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6

(2015) E. K. Ziemke et al.   CLINICAL CANCER RESEARCH

RAS Synthetic Lethal Screens Revisited: Still Seeking the Elusive Prize?

(2015) J. Downward   CLINICAL CANCER RESEARCH

SHP2 sails from physiology to pathology

(2015) Mylène Tajan et al.   European Journal of Medical Genetics

Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer

(2015) Khanh Do et al.   INVESTIGATIONAL NEW DRUGS

Multi-institutional Oncogenic Driver Mutation Analysis in Lung Adenocarcinoma: The Lung Cancer Mutation Consortium Experience

(2015) Lynette M. Sholl et al.   Journal of Thoracic Oncology

Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations

(2015) J. C. Hunter et al.   MOLECULAR CANCER RESEARCH

Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib

(2015) Caroline Robert et al.   NEW ENGLAND JOURNAL OF MEDICINE

A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors

(2014) A. W. Tolcher et al.   ANNALS OF ONCOLOGY

Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer

(2014) Avnish Kapoor et al.   CELL

Intrinsic Resistance to MEK Inhibition in KRAS Mutant Lung and Colon Cancer through Transcriptional Induction of ERBB3

(2014) Chong Sun et al.   Cell Reports

Requirement for Interaction of PI3-Kinase p110α with RAS in Lung Tumor Maintenance

(2013) Esther Castellano et al.   CANCER CELL

Genetically engineered mouse models of pancreatic adenocarcinoma

(2013) Carmen Guerra et al.   Molecular Oncology

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

Coordinate Direct Input of Both KRAS and IGF1 Receptor to Activation of PI3 kinase in KRAS -Mutant Lung Cancer

(2013) Miriam Molina-Arcas 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

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

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

Synthetic Lethal Interaction of Combined BCL-XL and MEK Inhibition Promotes Tumor Regressions in KRAS Mutant Cancer Models

(2012) Ryan B. Corcoran et al.   CANCER CELL

A Comprehensive Survey of Ras Mutations in Cancer

(2012) I. A. Prior et al.   CANCER RESEARCH

Molecular Epidemiology of EGFR and KRAS Mutations in 3,026 Lung Adenocarcinomas: Higher Susceptibility of Women to Smoking-Related KRAS-Mutant Cancers

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

KRAS Mutations in Lung Cancer

(2012) Niki Karachaliou et al.   Clinical Lung Cancer

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

ERK Inhibition Overcomes Acquired Resistance to MEK Inhibitors

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

Systematic identification of genomic markers of drug sensitivity in cancer cells

(2012) Mathew J. Garnett et al.   NATURE

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

Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers

(2011) Hiromichi Ebi et al.   JOURNAL OF CLINICAL INVESTIGATION

New driver mutations in non-small-cell lung cancer

(2011) William Pao et al.   LANCET ONCOLOGY

Regulating the regulator: post-translational modification of RAS

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

A Synthetic Lethal Interaction between K-Ras Oncogenes and Cdk4 Unveils a Therapeutic Strategy for Non-small Cell Lung Carcinoma

(2010) Marta Puyol et al.   CANCER CELL

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

Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers

(2008) Jeffrey A Engelman et al.   NATURE MEDICINE