The KRASG12D inhibitor MRTX1133 elucidates KRAS-mediated oncogenesis

doi:10.1038/s41591-022-02008-6

Cited by 35Protein Kinase Regulation and GTPase SignalingMelanoma and MAPK PathwaysProtein Tyrosine Phosphatases

The KRASG12D inhibitor MRTX1133 elucidates KRAS-mediated oncogenesis

·2022·Nature Medicine

DOI 10.1038/s41591-022-02008-6

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MRTX1133 inhibits KRAS signaling (pERK) in KRASG12D mutant cancer cell lines with IC50 values ranging from 0.6 nM to 13.7 nM (median 6.1 nM), while IC50 values in non-mutant KRASG12D cell lines range from 151 nM to over 3000 nM.
“Following a three-hour treatment on mutant KRASG12D cancer cell lines HPAC (pancreatic) and GP2D (colorectal), MRTX1133 caused inhibition (concentration-dependent) of key signaling molecules in the KRAS pathway, including phospho-ERK (pERK) [38,39], with IC50 values ranging from 0.6 nM to 13.7 nM (median IC50: 6.1 nM). In contrast, IC50 values ranged from 151 nM to over 3000 nM (median IC50: >3000”
From KRAS, a New Target for Precision Medicine in Colorectal Cancer? (2024) · cites this paper as [39]
MRTX1133 inhibited 2D and 3D KRASG12D cell lines with IC50 values ranging from 1.4 nM to 42.3 nM (3D) and between 1.5 nM and 299 nM (2D).
“Assessing cell viability, MRTX1133 inhibited both 2D and 3D KRASG12D cell lines with IC50 values ranging from 1.4 nM to 42.3 nM (3D) and between 1.5 nM and 299 nM (2D).”
From KRAS, a New Target for Precision Medicine in Colorectal Cancer? (2024) · cites this paper as [39]
MRTX1133 antitumor activity was particularly significant in pancreatic cancer models, where 8 out of 11 (73%) models exhibited tumor regression of 30% or more.
“This antitumor activity was particularly significant in pancreatic cancer models, where 8 out of 11 (73%) models exhibited tumor regression of 30% or more [39].”
From KRAS, a New Target for Precision Medicine in Colorectal Cancer? (2024) · cites this paper as [39]
MRTX1133 induced tumor regression of 30% or more in 11 out of 25 KRASG12D mutant models (PDX or cell lines).
“MRTX1133 induced tumor regression of 30% or more in 11 out of 25 KRASG12D mutant models (PDX or cell lines) [39].”
From KRAS, a New Target for Precision Medicine in Colorectal Cancer? (2024) · cites this paper as [39]

ras oncogenes in human cancer: a review.
Bos, J. L. (1989) · PubMed · Cited by 5,061 · see citing works
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Abstract 1131: Pharmacogenomic insight into targetable vulnerabilities and modifiers of response to MRTX1133 in KRASG12D-mutant models
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Venue: Nature Medicine
Publisher: Springer Science and Business Media LLC
Published: 2022-10
Volume: 28
Issue: 10
Pages: 2017-2018
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/s41591-022-02008-6
OpenAlex: W4303446440
Semantic Scholar: cafc712cb445a87f9335b8b9d1b4ea413ae4b54d
Cited by: 35
References: 5
Citations by year: 2026: 3 · 2025: 11 · 2024: 11 · 2023: 9 · 2022: 1
FWCI: 2.61
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Medicine (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 › Melanoma and MAPK Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords: MRTX1133, KRAS G12D, KRAS inhibitors, KRAS signaling, tumor regression, xenograft models, small molecule inhibitors
MeSH terms: Humans, Mutation, Pancreatic Neoplasms, Genes, ras, Proto-Oncogene Proteins p21(ras), Carcinogenesis

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The KRASG12D inhibitor MRTX1133 elucidates KRAS-mediated oncogenesis

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