TY - JOUR
T1 - KRAS
T2 - From undruggable to a druggable Cancer Target
AU - Uprety, Dipesh
AU - Adjei, Alex A.
N1 - Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/9
Y1 - 2020/9
N2 - 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.
AB - 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.
KW - Cancers
KW - Druggable
KW - G12C
KW - K-RAS
KW - Kras
KW - Undruggable
UR - http://www.scopus.com/inward/record.url?scp=85088314098&partnerID=8YFLogxK
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U2 - 10.1016/j.ctrv.2020.102070
DO - 10.1016/j.ctrv.2020.102070
M3 - Review article
C2 - 32711246
AN - SCOPUS:85088314098
SN - 0305-7372
VL - 89
JO - Cancer Treatment Reviews
JF - Cancer Treatment Reviews
M1 - 102070
ER -