RAS, wanted dead or alive: Advances in targeting RAS mutant cancers

Cancer statistics, 2019

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

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Drugging the undruggable RAS: Mission Possible?

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The Ras-RasGAP Complex: Structural Basis for GTPase Activation and Its Loss in Oncogenic Ras Mutants

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Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor

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Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations

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Association of KRAS p.G13D Mutation with Outcome in Patients with Chemotherapy-Refractory Metastatic Colorectal Cancer Treated with Cetuximab

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

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Project DRIVE: a compendium of cancer dependencies and synthetic lethal relationships uncovered by large-scale, deep RNAi screening

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

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Tumor adaptation and resistance to RAF inhibitors

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Ras Isoforms Vary in Their Ability to Activate Raf-1 and Phosphoinositide 3-Kinase

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Drugging an undruggable pocket on KRAS

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The Clinical Effect of the Dual-Targeting Strategy Involving PI3K/AKT/mTOR and RAS/MEK/ERK Pathways in Patients with Advanced Cancer

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

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KRAS Alleles: The Devil Is in the Detail

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Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase

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SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo

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Tumour maintenance is mediated by eNOS

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Intra-mitochondrial Poly(ADP-ribosylation) Contributes to NAD+ Depletion and Cell Death Induced by Oxidative Stress

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The Strange Case of CDK4/6 Inhibitors: Mechanisms, Resistance, and Combination Strategies

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Inhibition of RAS function through targeting an allosteric regulatory site

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

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Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers

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KRAS Suppression-Induced Degradation of MYC Is Antagonized by a MEK5-ERK5 Compensatory Mechanism

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KRAS ^G12C inhibition produces a driver-limited state revealing collateral dependencies

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Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule <i>KRAS^G12C</i> inhibitor, in advanced solid tumors.

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

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Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes

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Wild-Type H- and N-Ras Promote Mutant K-Ras-Driven Tumorigenesis by Modulating the DNA Damage Response

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MYC regulates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma associated with poor outcome and chemoresistance

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The role of wild type RAS isoforms in cancer

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Regulation of Ras Signaling Dynamics by Sos-Mediated Positive Feedback

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Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange

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Isoform-Specific Destabilization of the Active Site Reveals a Molecular Mechanism of Intrinsic Activation of KRas G13D

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RAF inhibitor LY3009120 sensitizes RAS or BRAF mutant cancer to CDK4/6 inhibition by abemaciclib via superior inhibition of phospho-RB and suppression of cyclin D1

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Application of a MYC degradation screen identifies sensitivity to CDK9 inhibitors in KRAS-mutant pancreatic cancer

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A systems mechanism for KRAS mutant allele–specific responses to targeted therapy

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Functional Redundancy of Sos1 and Sos2 for Lymphopoiesis and Organismal Homeostasis and Survival

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Response to Cetuximab With or Without Irinotecan in Patients With Refractory Metastatic Colorectal Cancer Harboring the KRAS G13D Mutation: Australasian Gastro-Intestinal Trials Group ICECREAM Study

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Oncogenic RAS isoforms show a hierarchical requirement for the guanine nucleotide exchange factor SOS2 to mediate cell transformation

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Combination of RAF and MEK Inhibition for the Treatment of BRAF-Mutated Melanoma: Feedback Is Not Encouraged

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Meta-analysis comparing the efficacy of anti-EGFR monoclonal antibody therapy between KRAS G13D and other KRAS mutant metastatic colorectal cancer tumours

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Disruption of the Interaction of RAS with PI 3-Kinase Induces Regression of EGFR-Mutant-Driven Lung Cancer

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The bacterial Ras/Rap1 site-specific endopeptidase RRSP cleaves Ras through an atypical mechanism to disrupt Ras-ERK signaling

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The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy

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The metabolic landscape of RAS-driven cancers from biology to therapy

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MAPK/ERK Signaling Pathway in Hepatocellular Carcinoma

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Pathological implication of protein post-translational modifications in cancer

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KRAS inhibitors: resistance drivers and combinatorial strategies

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The path to the clinic: a comprehensive review on direct KRASG12C inhibitors

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E3 ligases and deubiquitinating enzymes regulating the MAPK signaling pathway in cancers

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Malignant peripheral nerve sheath tumor: models, biology, and translation

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The Importance of Being PI3K in the RAS Signaling Network

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Epithelial and stromal co-evolution and complicity in pancreatic cancer

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SOS GEFs in health and disease

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Scaffold proteins as dynamic integrators of biological processes

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New Model Systems and the Development of Targeted Therapies for the Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors

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An Emerging Role for the Unfolded Protein Response in Pancreatic Cancer

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Targeting farnesylation as a novel therapeutic approach in HRAS-mutant rhabdomyosarcoma

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Divergent Mechanisms Activating RAS and Small GTPases Through Post-translational Modification

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Global Phosphoproteomics Reveal CDK Suppression as a Vulnerability to KRas Addiction in Pancreatic Cancer

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Targeting RAS oncogenesis with SOS1 inhibitors

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Novel regulation of Ras proteins by direct tyrosine phosphorylation and dephosphorylation

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Neurofibromatosis in the Era of Precision Medicine: Development of MEK Inhibitors and Recent Successes with Selumetinib

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Prevalence of KRAS p.(G12C) in stage IV NSCLC patients in the Netherlands; a nation-wide retrospective cohort study

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The KRAS-regulated kinome identifies WEE1 and ERK coinhibition as a potential therapeutic strategy in KRAS-mutant pancreatic cancer

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Structure-based inhibitor design of mutant RAS proteins—a paradigm shift

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Dysregulated KRAS gene-signaling axis and abnormal chromatin remodeling drive therapeutic resistance in heterogeneous-sized circulating tumor cells in gastric cancer patients

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A Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth and Induces Antitumor Immunity in Gastrointestinal Cancer

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Clinical and Molecular Features of KRAS-Mutated Lung Cancer Patients Treated with Immune Checkpoint Inhibitors

Zhao, D., Li, H., Mambetsariev, I., Mirzapoiazova, T., Chen, C., Fricke, J., Kulkarni, P., Villaflor, V., Arvanitis, L., Hamilton, S., et al. (2022) · Cancers · doi:10.3390/cancers14194933 · Cited by 24 · see citing works

Identification of the nucleotide-free state as a therapeutic vulnerability for inhibition of selected oncogenic RAS mutants

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Multitargeting HDAC Inhibitors Containing a RAS/RAF Protein Interfering Unit

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Drivers of Gene Expression Dysregulation in Pancreatic Cancer

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KRAS-related long noncoding RNAs in human cancers

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Fluorescent Biosensor for Measuring Ras Activity in Living Cells

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Oncogenic RAS promotes MYC protein stability by upregulating the expression of the inhibitor of apoptosis protein family member Survivin

Chang, W.-H., Liu, Y., Hammes, E. A., Bryant, K. L., Cerione, R. A., & Antonyak, M. A. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102842 · Cited by 21 · see citing works

One Step at a Time — Clinical Evidence That KRAS Is Indeed Druggable

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A brief history of RAS and the RAS Initiative

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Discovery of KRB-456, a KRAS G12D Switch-I/II Allosteric Pocket Binder That Inhibits the Growth of Pancreatic Cancer Patient-derived Tumors

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NF1 loss of function as an alternative initiating event in pancreatic ductal adenocarcinoma

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Targeting RAF dimers in RAS mutant tumors: From biology to clinic

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A Review on Exploring the Opportunities of Polymer Drug Conjugated Systems for Targeted Cancer Treatment

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SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers

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Targeting RNA helicase DHX33 blocks Ras‐driven lung tumorigenesis in vivo

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p65BTK Is a Novel Biomarker and Therapeutic Target in Solid Tumors

Grassilli, E., Cerrito, M. G., Bonomo, S., Giovannoni, R., Conconi, D., & Lavitrano, M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.690365 · Cited by 15 · see citing works

Targeting copper metabolism to defeat KRAS-driven colorectal cancer

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A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer

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Design, synthesis, and evaluation of 4(1H)-quinolinone and urea derivatives as KRASG12C inhibitors with potent antitumor activity against KRAS-mutant non-small cell lung cancer

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Analysis of KRAS–Ligand Interaction Modes and Flexibilities Reveals the Binding Characteristics

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Proximal Protein Interaction Landscape of RAS Paralogs

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Rapid Improvement of the Performance Status and Reduction of the Tumor Size in KRAS-Mutated Colorectal Cancer Patient Receiving Binimetinib, Hydroxychloroquine, and Bevacizumab

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Divergent Functions of Rap1A and Rap1B in Endothelial Biology and Disease

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A bedside-to-bench translational analysis of NF1 alterations and CDK4/6 inhibitor resistance in hormone receptor-positive metastatic breast cancer

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Stromal-Derived Extracellular Vesicles Suppress Proliferation of Bone Metastatic Cancer Cells Mediated by ERK2

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KRAS, NRAS, BRAF signatures, and MMR status in colorectal cancer patients in North China

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K-RAS4A: Lead or Supporting Role in Cancer Biology?

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SFPQ promotes RAS-mutant cancer cell growth by modulating 5′-UTR mediated translational control of CK1α

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Metabolic and Regulatory Pathways Involved in the Anticancer Activity of Perillyl Alcohol: A Scoping Review of In Vitro Studies

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Design, synthesis and biological evaluation of pyrrolopyrimidine urea derivatives as novel KRASG12C inhibitors for the treatment of cancer

Shang, Y., Pang, M., Fu, S., Fei, W., Chen, B.-X., Zhang, Y., Wang, J., & Shen, T. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117391 · Cited by 7 · see citing works

Structural insights, regulation, and recent advances of RAS inhibitors in the MAPK signaling cascade: a medicinal chemistry perspective

Prajapati, V., Singh, A. K., Kumar, A. M., Singh, H., Pathak, P., Grishina, M., Kumar, V., Khalilullah, H., Verma, A., & Kumar, P. (2025) · RSC Medicinal Chemistry · doi:10.1039/d4md00923a · Cited by 6 · see citing works

Evaluation of the RAS signaling network in response to MEK inhibition using organoids derived from a familial adenomatous polyposis patient

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Anthraquinones as Inhibitors of SOS RAS-GEF Activity

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RET mutated C-cells proliferate more rapidly than non-mutated neoplastic cells

Romei, C., Ramone, T., Mulè, C., Prete, A., Cappagli, V., Lorusso, L., Torregrossa, L., Basolo, F., Ciampi, R., & Elisei, R. (2021) · Endocrine Connections · doi:10.1530/ec-20-0589 · Cited by 6 · see citing works

Interferon-Induced Transmembrane Protein 1 (IFITM1) Is Downregulated in Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors

Park, G.-H., Park, E., Lee, S.-J., Lim, K., Kim, J., Park, J. E., & Jeong, S. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25179265 · Cited by 5 · see citing works

Targeting Kinase Suppressor of Ras 1 (KSR1) for Cancer Therapy

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Genetically encodable biosensors for Ras activity

Weeks, R., Mehta, S., & Zhang, J. (2024) · RSC Chemical Biology · doi:10.1039/d3cb00185g · Cited by 4 · see citing works

Grifolin Induces Cell Death of Human Lung Cancer A549 Cell Line via Inhibiting KRAS‐Mediated Multiple Signaling Pathways

Zhao, X., Ma, R., Liu, H., Shan, P., Bao, J., & Zhang, H. (2024) · Chemistry & Biodiversity · doi:10.1002/cbdv.202400792 · Cited by 4 · see citing works

Exploring the state- and allele-specific conformational landscapes of Ras: understanding their respective druggabilities

Wang, H., Liu, D., Yu, Y., Fang, M., Gu, X., & Long, D. (2022) · Physical Chemistry Chemical Physics · doi:10.1039/d2cp04964c · Cited by 4 · see citing works

RAS GTPases and Interleaflet Coupling in the Plasma MembranePreprint

Liu, J., Arora, N., & Zhou, Y. (2023) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a041414 · Cited by 5 · see citing works

KRAS mutations in colorectal cancer: impacts on tumor microenvironment and therapeutic implications

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The Role of Genetics and Synergistic Effect of Targeting Common Genetic Mutations in Acute Lymphoblastic Leukemia (ALL)

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Cardio-Facio-Cutaneous Syndrome

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A signalling cascade for Ral

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Allosteric inhibitors for the treatment of cancers (2021-): A review from medicinal chemistry perspectives

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Targeting RAS-mutant cancer cells using a synthetic RAS-activated cancer killing system

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Harnessing Antibody-Mimetic Selectivity for Activation-State-Specific Targeted Degradation of Endogenous K-Ras

Ferguson, F. M. (2021) · ACS Central Science · doi:10.1021/acscentsci.1c00084 · Cited by 2 · see citing works

Fatal abdominal hemorrhage following surgery to remove a retroperitoneal MPNST associated with NF1: A case report

Pei, Y.-Y., Yang, T., Zhang, H., & Yu, T.-S. (2024) · Medicine · doi:10.1097/md.0000000000040745 · Cited by 1 · see citing works

A Novel Prognostic Risk‐Scoring Model Based on RAS Gene‐Associated Cluster in Pediatric Acute Myeloid Leukemia

Luo, C., Abudukeremu, Y., Rao, M., Zhou, D., Fang, J., Li, Y., & Xu, L. (2025) · Cancer Medicine · doi:10.1002/cam4.70716 · Cited by 1 · see citing works

Ras and Ras Signaling as a Therapeutic Target in Cancer

Sliker, B. H., & Campbell, P. M. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820472-6.00006-2

Defining the KRAS-regulated kinome in KRAS-mutant pancreatic cancerPreprint

Diehl, J. N., Klomp, J. E., Snare, K. R., Blake, D. R., Hibshman, P. S., Kaiser, Z. D., Gilbert, T. S. K., Baldelli, E., Pierobon, M., Papke, B., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.04.27.441678

Characteristics and therapy of advanced cancer diseases

Taghizadeh, H. (2021)

Brain I3 Binding Protein regulates K-Ras4B membrane localization and signalingPreprint

McCabe, I. P., Zhang, H., Cooper, J. A., Turner, D. L., & Vojtek, A. B. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.09.21.461216

Targeting a broad spectrum of KRAS -mutant cancers by hyperactivation-induced cell deathPreprint

Lilja, J., Kaivola, J., Conway, J. R. W., Vuorio, J., Parkkola, H., Roivas, P., Varila, T., Jacquemet, G., Peuhu, E., Wang, E., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.21.508660

Cancer Disease-Oriented-Drug Development Examples

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Data from Global Phosphoproteomics Reveal CDK Suppression as a Vulnerability to KRas Addiction in Pancreatic Cancer

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Loss of Golga7 Suppresses Oncogenic Nras ‐Driven Leukemogenesis without Detectable Toxicity in Adult Mice

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The Ral small GTPase is an essential regulator of exocyst complex function in secretion

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Unraveling the Impact of KRAS Accessory Proteins on Oncogenic Signaling Pathways

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Pan-cancer perspectives on post-translational modifications and metastasis: Unraveling complex molecular mechanisms

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High-throughput screening identifies NT-1 that synergizes with MRTX1133 against acquired resistant KRASG12D colorectal cancer

Thielen, N., Wei, N., Nagai, E., Houston, M. A., Augenlicht, L. H., Shin, A. E., Gabre, J. T., Rustgi, A. K., Ha, G., LaFave, L. M., et al. (2026) · npj Precision Oncology · doi:10.1038/s41698-026-01384-3

Carbohydrates metabolic reprogramming and tumor microenvironment in pancreatic cancer: targeting pathways

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Oncogenic RAS as an adaptive signaling ecosystem: context-dependent vulnerabilities and resistance-informed therapeutic design

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BindingDB Entry 50023564: Design, synthesis and biological evaluation of pyrrolopyrimidine urea derivatives as novel KRASG12C inhibitors for the treatment of cancer.

BindingDB (2026) · UC San Diego · doi:10.7270/q2445sck

BindingDB Entry 50021644: Multitargeting HDAC Inhibitors Containing a RAS/RAF Protein Interfering Unit.

BindingDB (2025) · UC San Diego · doi:10.7270/q2668jtz

The role of wild-type RAS in oncogenic RAS transformation

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The RAS–Effector Interaction as a Drug Target

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Wild-type RAS signaling is an essential therapeutic target in RAS -mutated cancers

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Mutations and Targeted Drugs Alter RAS Signaling Dynamics in Cancer

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