KRAS: From undruggable to a druggable Cancer Target

Uprety, Dipesh; Adjei, Alex A.

doi:10.1016/j.ctrv.2020.102070

Cited by 273Protein Kinase Regulation and GTPase SignalingProtein Tyrosine PhosphatasesMelanoma and MAPK Pathways

KRAS: From undruggable to a druggable Cancer Target

Uprety, Dipesh, Adjei, Alex A.·2020·Cancer Treatment Reviews

DOI 10.1016/j.ctrv.2020.102070

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Abstract

RAS is the most frequently mutated oncogene in human cancers, with mutations in about 30% of all cancers. RAS exists in three different isoforms (K-RAS, H-RAS and N-RAS) with high sequence homology. K-RAS is the most commonly mutated RAS isoform. The Ras protein is a membrane bound protein with inherent GTPase activity and is activated by numerous extracellular stimuli, cycling between an inactive (GDP-bound) and active (GTP-bound) form. When bound to GTP, it is switched "on" and activates intracellular signaling pathways, critical for cell proliferation and angiogenesis. Mutated RAS is constitutively activated and persistently turned "on" thereby enhancing downstream signaling and leading to tumorigenesis. Various attempts to inhibit Kras in the past were unsuccessful. Recently, several small molecules (AMG510, MRTX849, JNJ-74699157, and LY3499446) have been developed to specifically target K-RAS G12C. Additionally, various other approaches including, SHP2, SOS1 and eIF4 inhibition, have been utilized to abrogate tumor growth in K-RAS mutant cells, resulting in a renewed interest in this pathway. In this review article, we provide an overview on the role of K-RAS in tumorigenesis, past approaches to inhibiting Kras, and current and future prospects for targeting Kras.

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JNJ-74699157 blocks downstream signaling of KRASG12C by covalently binding to the KRASG12C complex near S-II P of the KRAS mutant protein.
“It blocks downstream signaling of KRASG12C by covalently binding to the KRASG12C complex near S-II P of the KRAS mutant protein.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [63]
JNJ-74699157 is a new generation, oral, selective, covalent inhibitor of the KRASG12C subtype developed by Wellspring.
“JNJ-74699157 (4), also called ARS-3248, is a new generation, oral, selective, covalent inhibitor of the KRASG12C subtype developed by this company.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [63]

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Different Patterns of Mast Cells Distinguish Diffuse from Encapsulated Neurofibromas in Patients with Neurofibromatosis 1
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Wajchenberg (2000) · doi:10.1002/(sici)1097-0142(20000215)88:4

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A Potent SOS1 PROTAC Degrader with Synergistic Efficacy in Combination with KRASG12C Inhibitor
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Advances in i-motif structures: Stability, gene expression, and therapeutic applications
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Integrated Molecular Analysis Reveals 2 Distinct Subtypes of Pure Seminoma of the Testis
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The Importance of Mg 2+ ‐Free State in Nucleotide Exchange of Oncogenic K‐Ras Mutants
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KRAS Mutation in Rare Tumors: A Landscape Analysis of 3453 Chinese Patients
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Inhibition of ULK1/2 and KRASG12C controls tumor growth in preclinical models of lung cancer
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Daily Practice Assessment of KRAS Status in NSCLC Patients: A New Challenge for the Thoracic Pathologist Is Right around the Corner
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Self-citation
Targeting KRAS in Cancer: Promising Therapeutic Strategies
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Ras and Ras Signaling as a Therapeutic Target in Cancer
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Authors: Uprety, D., & Adjei, A. A.
Affiliations: Mayo Clinic (US)
Corresponding author: Adjei, Alex A.
ORCID: Uprety, Dipesh
Adjei, Alex A.
Venue: Cancer Treatment Reviews
Publisher: Elsevier BV
Published: 2020-09
Volume: 89
Pages: 102070
ISSN: 0305-7372 (ISSN-L)
DOI: 10.1016/j.ctrv.2020.102070
OpenAlex: W3042326408
Semantic Scholar: 87b920c05dc5abe58478390ddd20a90e6ac26cd4
Cited by: 271
References: 204
Citations by year: 2026: 23 · 2025: 46 · 2024: 64 · 2023: 49 · 2022: 50 · 2021: 38 · 2020: 1
FWCI: 3.33
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Cancer Treatment Reviews (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Keywords: KRAS, oncogenic Ras, sotorasib, adagrasib, SHP2 inhibition, SOS1 inhibition, carcinogenesis, Ras signaling
MeSH terms: Animals, Humans, Mutation, Neoplasms, Signal Transduction, Proto-Oncogene Proteins p21(ras), Molecular Targeted Therapy

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KRAS: From undruggable to a druggable Cancer Target

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