Targeting RAS mutants in malignancies: successes, failures, and reasons for hope

Yang, Hang; Zhou, Xinyi; Fu, Dongliang; Le, Chenqin; Wang, Jiafeng; Zhou, Quan; Liu, Xiangrui; Yuan, Ying; Ding, Kefeng; Xiao, Qian

doi:10.1002/cac2.12377

Cited by 20 publications

(21 citation statements)

References 296 publications

(363 reference statements)

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“…The recent development of RAS inhibitors marks a milestone and promises a brighter future for many cancer patients. It also redefines the current and future challenges, including improving inhibitor efficacies, mitigating acquired resistance, and developing new inhibitors that cover all oncogenic RAS isoforms (11,31,32). To address these issues, obtaining better insights into the mechanisms of oncogenic RAS signalling is essential.…”

Section: Discussionmentioning

confidence: 99%

Endogenous oncogenic KRAS expression increases cell proliferation and motility in near-diploid hTERT RPE-1 cells

Hindul,

Abbott,

Adan

et al. 2023

Preprint

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About 18% of all human cancers carry a mutation in the KRAS gene making it among the most sought-after anti-cancer targets. However, mutant KRas protein has proved remarkably undruggable. The recent approval of the first generation of RAS inhibitors therefore marks a seminal milestone in the history of cancer research. Inevitably though, it also raises the predictable challenges of limited drug efficacies and acquired resistance. Hence, new approaches that improve our understanding of the tumorigenic mechanisms of oncogenic RAS within more physiological settings continue to be essential. Here, we have employed the near-diploid human hTERT RPE-1 cells to generate isogenic cell lines in which one of the endogenous KRAS alleles carries an oncogenic KRAS mutation at glycine 12. Cells with a KRASG12V/+, KRASG12C/+, or KRASG12D/+ genotype, together with wild-type KRASG12G(WT)/+ cells, reveal that oncogenic KRAS.G12X mutations increase cell proliferation rate, while further analyses showed that KRASG12V/+ cells had increased cell motility and reduced focal adhesions. EGF-induced ERK phosphorylation was marginally increased in KRASG12V/+ cells, while EGF-induced AKT phosphorylation was comparable between KRASG12V/+ and KRASG12G(WT)/+ cells. Interestingly, the KRASG12V/+ cells were more sensitive to hydroxyurea and a MEK inhibitor, U0126, but more resistant to a PI3K inhibitor, PIK-90, than the KRASG12G(WT)/+ cells. A combination of low doses of hydroxyurea and U0126 showed an additive inhibition on growth rate that was greater in KRASG12V/+ than wild-type cells. Collectively, these cell lines will be a valuable resource for studying oncogenic RAS signalling and developing effective anti-KRAS reagents with minimum cytotoxicity on wild-type cells.

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Section: Discussionmentioning

confidence: 99%

Endogenous oncogenic KRAS expression increases cell proliferation and motility in near-diploid hTERT RPE-1 cells

Hindul,

Abbott,

Adan

et al. 2023

Preprint

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show abstract

“…1 (8). 1 General Procedure for the Synthesis of Compounds 10−12. To a solution of 38a (200 mg, 0.5 mmol; 1.0 equiv) in 10 mL DCE was added tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (41) (105 mg, 0.5 mmol; 1.0 equiv).…”

Section: -((8-((2-(5-((r)-1-((67-dimethoxy-2-methylquinazolin-4-yl)am...mentioning

confidence: 99%

“…1 (13). 1 General Procedure for the Synthesis of Compound 12. Compound 45 was synthesized from V1 and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid following the process of Method 2 in 68% yield.…”

Section: (2s4r)-1-((s)-2-(8-((2-(5-((r)-1-((67-dimethoxymentioning

confidence: 99%

“…NMR (400 MHz, DMSO-d 6 ) δ 8.95 (s, 1H), 8.58 (t, J = 6.1 Hz, 1H), 8.41 (d, J = 8.1 Hz, 1H), 8.15 (s, 1H), 8.10−8.03 (m, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.67 (s, 1H), 7.48−7.24 (m, 9H), 7.18 (s, 1H), 7.01 (s, 1H), 5.92 (p, J = 7.2 Hz, 1H), 5.87−5.81 (m, 1H), 4.50 (d, J = 9.3 Hz, 1H), 4.44−4.35 (m, 2H), 4.31 (s, 1H), 4.22−4.15 (m, 1H), 4.13−4.04 (m, 2H), 4.02 (s, 2H), 3.83 (s, 3H), 3.67−3.55 (m, 8H), 2.65−2.54 (m, 2H), 2.43−2.39 (m, 9H), 2.06−1.81 (m, 2H), 1.67 (d, J = 6.9 Hz, 3H), 0.91 (s, 9H) ppm. (2S,4R)-4-Hydroxy-1-((S)-2-(5-(4-(7-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)-3,6-dihydropyridin-1(2H)-yl)-5-oxopentanamido)-3,3dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(15) 1. H NMR (400 MHz, DMSO-d 6 ) δ 8.94 (s, 1H), 8.77 (s, 1H), 8.56 (t, J = 6.0 Hz, 1H), 8.11 (s, 1H), 7.94−7.86 (m, 1H), 7.63−7.55 (m, 1H), 7.46−7.29 (m, 9H), 7.17 (s, 1H), 7.05 (s, 1H), 5.95 (p, J = 7.2 Hz, 1H), 5.88−5.82 (m, 1H), 5.14 (s, 1H), 4.51 (d, J = 9.2 Hz, 1H), 4.43−4.35 (m, 2H), 4.32 (s, 1H), 4.21−4.14 (m, 1H), 4.11 (s, 2H), 4.09−4.05 (m, 2H), 3.84 (s, 3H), 3.68−3.52 (m, 8H), 2.47−2.45 (m, 6H), 2.40 (s, 3H), 2.35−2.25 (m, 3H), 2.22−2.14 (m, 1H), 2.05−1.94 (m, 1H), 1.90−1.82 (m, 1H), 1.69 (d, J = 7.0 Hz, 3H), 0.91 (s, 9H) ppm.…”

mentioning

confidence: 99%

“…1 H NMR (400 MHz, DMSOd 6 ) δ 9.90 (d, J = 8.0 Hz, 1H), 9.03−8.94 (m, 3H), 8.57 (t, J = 6 1. Hz, 1H), 7.95−7.88 (m, 2H), 7.60−7.55 (m, 1H), 7.48 (s, 1H), 7.44−7.37 (m, 4H), 7.36−7.32 (m, 3H), 7.25 (s, 1H), 7.21 (s, 1H), 6.07 (q, J = 7.1 Hz, 1H), 4.52 (d, J = 9.3 Hz, 1H), 4.44−4.35 (m, 2H), 4.31 (s, 1H), 4.18 (dd, J = 15.8, 5.4 Hz, 1H), 4.12 (t, J = 6.1 Hz, 2H), 4.05 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 3.68−3.57 (m, 2H), 2.62 (s, 3H), 2.47−2.46 (m, 2H), 2.40 (s, 3H), 2.38−2.29 (m, 1H), 2.25−2.14 (m, 1H), 2.05−1.96 (m, 1H), 1.91−1.82 (m, 1H), 1.78−1.72 (m, 5H), 1.69−1.59 (m, 2H), 0.90 (s, 9H)ppm.…”

mentioning

confidence: 99%

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A Potent SOS1 PROTAC Degrader with Synergistic Efficacy in Combination with KRAS^G12C Inhibitor

Lv,

Yang,

Chen

et al. 2024

J. Med. Chem.

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AMG510, as the first approved inhibitor for KRAS G12C mutation, has shown promising efficacy in nonsmallcell lung cancer and colorectal cancer harboring KRAS G12C mutation. However, the moderate response rate and the rapid emergence of acquired resistance limit the therapeutic potential of AMG510, highlighting the need for the development of combination strategies. Here, we observed the suppression of RAS-MAPK signaling induced by AMG510 was prolonged and enhanced by SOS1 knockdown. Thus, we design, synthesize, and characterize a potent and specific SOS1 degrader 23. Compound 23 showed efficient SOS1 degradation in KRAS-driven cancer cells and achieved significant antiproliferative potency. Importantly, the combination of 23 with AMG510 suppressed RAS signaling feedback activation, showing synergistic effects against KRAS G12C mutant cells in vitro and in vivo. Our findings demonstrated that KRAS G12C inhibition plus SOS1 degradation as a potential therapeutic strategy to improve antitumor response and overcome acquired resistance to KRAS G12C inhibitor.

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Targeting RAS mutants in malignancies: successes, failures, and reasons for hope

Yang

Zhou

et al. 2022

Cancer Communications

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RAS genes are the most frequently mutated oncogenes and play critical roles in the development and progression of malignancies. The mutation, isoform ( KRAS , HRAS , and NRAS ), position, and type of substitution vary depending on the tissue types. Despite decades of developing RAS‐targeted therapies, only small subsets of these inhibitors are clinically effective, such as the allele‐specific inhibitors against KRAS G12C . Targeting the remaining RAS mutants would require further experimental elucidation of RAS signal transduction, RAS‐altered metabolism, and the associated immune microenvironment. This study reviews the mechanisms and efficacy of novel targeted therapies for different RAS mutants, including KRAS allele‐specific inhibitors, combination therapies, immunotherapies, and metabolism‐associated therapies.

show abstract

Targeting RAS mutants in malignancies: successes, failures, and reasons for hope

Cited by 20 publications

References 296 publications

Endogenous oncogenic KRAS expression increases cell proliferation and motility in near-diploid hTERT RPE-1 cells

Endogenous oncogenic KRAS expression increases cell proliferation and motility in near-diploid hTERT RPE-1 cells

A Potent SOS1 PROTAC Degrader with Synergistic Efficacy in Combination with KRAS^G12C Inhibitor

Targeting RAS mutants in malignancies: successes, failures, and reasons for hope

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Targeting RAS mutants in malignancies: successes, failures, and reasons for hope

Cited by 20 publications

References 296 publications

Endogenous oncogenic KRAS expression increases cell proliferation and motility in near-diploid hTERT RPE-1 cells

Endogenous oncogenic KRAS expression increases cell proliferation and motility in near-diploid hTERT RPE-1 cells

A Potent SOS1 PROTAC Degrader with Synergistic Efficacy in Combination with KRASG12C Inhibitor

Targeting RAS mutants in malignancies: successes, failures, and reasons for hope

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A Potent SOS1 PROTAC Degrader with Synergistic Efficacy in Combination with KRAS^G12C Inhibitor