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The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients
Open accessPublished version of a preprint
Abstract
Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identified as a potent, selective, and covalent KRASG12C inhibitor that exhibits favorable drug-like properties, selectively modifies mutant cysteine 12 in GDP-bound KRASG12C, and inhibits KRAS-dependent signaling. MRTX849 demonstrated pronounced tumor regression in 17 of 26 (65%) KRASG12C-positive cell line– and patient-derived xenograft models from multiple tumor types, and objective responses have been observed in patients with KRASG12C-positive lung and colon adenocarcinomas. Comprehensive pharmacodynamic and pharmacogenomic profiling in sensitive and partially resistant nonclinical models identified mechanisms implicated in limiting antitumor activity including KRAS nucleotide cycling and pathways that induce feedback reactivation and/or bypass KRAS dependence. These factors included activation of receptor tyrosine kinases (RTK), bypass of KRAS dependence, and genetic dysregulation of cell cycle. Combinations of MRTX849 with agents that target RTKs, mTOR, or cell cycle demonstrated enhanced response and marked tumor regression in several tumor models, including MRTX849-refractory models. Significance: The discovery of MRTX849 provides a long-awaited opportunity to selectively target KRASG12C in patients. The in-depth characterization of MRTX849 activity, elucidation of response and resistance mechanisms, and identification of effective combinations provide new insight toward KRAS dependence and the rational development of this class of agents. See related commentary by Klempner and Hata, p. 20. This article is highlighted in the In This Issue feature, p. 1
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The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Adagrasib has favorable pharmacokinetic properties, including a long half-life (23 hours), dose-dependent pharmacokinetics, and central nervous system (CNS) penetration.8,21,22”
From Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C (2023) · cites this paper as [8]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The KRAS glycine-to-cysteine mutation at codon 12 (KRAS G12C) occurs in 3 to 4% of patients with colorectal cancer and impairs GTP hydrolysis, which shifts KRAS to the active GTP-binding state to drive protumorigenic effector signaling.8,10–12”
From Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C (2023) · cites this paper as [8]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Maintaining continuous adagrasib exposure above a target threshold allows for the inhibition of KRAS-dependent signaling for the duration of the dosing interval and is predicted to maximize antitumor activity.8,20”
From Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C (2023) · cites this paper as [8]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Despite the clinical benefit that was observed for many patients treated with KRASG12C inhibitors, acquired resistance to single-agent therapy eventually occurred in most patients.”
From Acquired Resistance to KRAS G12C Inhibition in Cancer (2021) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In early-phase clinical trials, two potent, selective, and irreversible small-molecule KRASG12C inhibitors have shown promising results in non–small-cell lung cancer (NSCLC) and more modest efficacy in colorectal cancer: adagrasib (MRTX849) and sotorasib (AMG510).6,7,10”
From Acquired Resistance to KRAS G12C Inhibition in Cancer (2021) · cites this paper as [7]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“One major route leading to such recovery of RAS activity is the activation of RTKs through either genetic (e.g., gene amplification or fusion) or non-genetic mechanisms.2,4,5,6,7,8,22,23,24,25”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [2]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Sotorasib and adagrasib, two prominent members of this class, were effective at halting the growth of G12C-mutant cancer cells in 2-dimensional, 3-dimensional, and xenograft models, clearing the path for clinical trials [48,49,50,51].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [50]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“These included ALK, APC, CDKN2A/B, CTNNB1, IDH1/2, KEAP1, MET, MYC, NRAS, PTCH1, PTEN, RB1, RET, RICTOR, SMARCA4, and TP53 [50,97,102].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [50]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“KRAS inhibition leads to short-term decreases in the expression of genes related to glycolysis, mitotic spindle formation, G2M checkpoint, and the downstream targets of E2F, MYC, and mTOR signaling [50].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [50]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“CRISPR screens using the KRAS G12C inhibitor adagrasib found the deletion of tumor suppressors KEAP1 and RB1 as mechanisms of resistance to KRAS inhibition in both in vitro and in vivo models [50].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [50]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The inhibition of mutant KRAS rapidly decreases the phosphorylation of MEK and ERK, leading to a decrease in the expression of nuclear ERK-regulated genes including DUSP proteins, RSK, MYC, SPRY1, and SPRED1 (Figure 2) [50,62].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [50]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Prior studies with KRAS G12C , RAF, and MEK inhibitors indicated that blockade of KRAS-dependent signaling activated a transcriptional program suppressing DUSP , SPRY , and ETV family genes which cooperate to mediate increased signaling flux though RTK, SOS, and MEK/ERK family members resulting in conditional bypass dependence on KRAS [4, 32-34].”
From Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor (2022) · cites this paper as [4]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, studies evaluating the anti-tumor activity of KRAS G12C inhibitors indicated that the dependence of cells on KRAS mutations for growth and survival as oncogenic drivers was distinct in in vitro cell lines compared with in vivo model systems ([4, 22]).”
From Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor (2022) · cites this paper as [4]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Clinical trials of multiple KRASG12C inhibitors have shown promising efficacy in advanced, previously treated non–small cell lung cancer (NSCLC), leading to United States Food and Drug Administration (FDA) accelerated approval of two of these therapies (adagrasib and sotorasib) and many others being investigated in this setting (9–17).”
From Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer (2024) · cites this paper as [9]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Recent studies using preclinical models have indicated that acquired resistance to KRASG12C inhibition may be mediated by the activation of multiple receptor tyrosine kinase (RTK) regulators, including epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), insulin-like growth factor 1 receptor (IGF1R), human epidermal growth factor 2 (HER2), and Src homology 2 domain-”
From Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers (2025) · cites this paper as [2]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Most KRAS G12C mutant non-small cell lung cancer (NSCLC) patients experience clinical benefit from selective KRAS G12C inhibition, while patients with colorectal cancer (CRC) bearing the same mutation rarely respond.”
From EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer. (2020) · cites this paper as [15]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Clinical trials results have shown limited efficacy of KRAS G12C covalent inhibitors in CRC; only one CRC patient treated with MRTX849 had a 47% tumor reduction by RECIST criteria(15).”
From EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer. (2020) · cites this paper as [15]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Previous studies evidenced that RTK/kinase feedback activation is among the main mechanisms of adaptive resistance to KRASG12C inhibitors”
From Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C -mutant Colorectal Cancer (2023) · cites this paper as [32]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“we found that sensitivity to AZ’1569 was not predicted by the KRAS allele zygosity status, the presence of concomitant mutations (including TP53 mutations), or baseline levels of kinases within the EGFR/KRAS axis”
From Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C -mutant Colorectal Cancer (2023) · cites this paper as [32]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer.”
From Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C (2023) · cites this paper as [8]
The cited source says what the claim attributes to it.
In the citing paper
“Adagrasib (MRTX849) is an orally available, small-molecule covalent inhibitor of KRAS G12C that irreversibly and selectively binds the mutant protein in its inactive, GDP-bound state.8,20”
From Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C (2023) · cites this paper as [8]
The cited source says what the claim attributes to it.
In the citing paper
“compounds have been identified that bind covalently to cysteine 12 within the switch II pocket of the GDP-bound form of the KRASG12C protein, preventing oncogenic signaling and causing potent tumor regressions in preclinical models.3-7”
From Acquired Resistance to KRAS G12C Inhibition in Cancer (2021) · cites this paper as [7]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Combining the mTOR inhibitor vistusertib with MRTX849 treatment showed strong synergy against a panel of sensitive cell lines and xenograft models [50].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [50]
The cited source says what the claim attributes to it.
In the citing paper
“SHP2 inhibitors synergize with KRAS G12C inhibitors against sensitive mouse tumors, possibly because they prevent feedback reactivation driven by the loss of ERK-mediated EGFR repression when KRAS activity is abrogated and/or because SHP2 inhibitors drive KRAS to be in the G12C inhibitor-sensitive GDP-bound state of KRAS [50,133].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [50]
The cited source says what the claim attributes to it.
In the citing paper
“However, covalent inhibitors targeting the mutated cysteine residues in KRAS G12C exploited a binding pocket in the switch II domain which enabled the development of clinically active small molecule inhibitors for patients with this mutation [3-5].”
From Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor (2022) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“Recent advances in medicinal chemistry have enabled the development of direct small-molecule inhibitors of KRAS, including covalent inhibitors of the KRASG12C protein that impair oncogenic signaling and cause tumor regressions in preclinical models (8–10).”
From Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer (2024) · cites this paper as [9]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“The mechanisms of acquired resistance to these therapies are currently unknown.”
From Acquired Resistance to KRAS G12C Inhibition in Cancer (2021) · cites this paper as [7]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“In 2021, the FDA approved sotorasib for the treatment of adult patients with KRAS G12C-mutated NSCLC, while adagrasib received similar approval the following year [48,50,51,52,53].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [50]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Studies conducted with MRTX849 in KRAS G12C mutated nonclinical tumor cell lines and in vivo models generally demonstrated a lack of effectiveness for the combination with BYL719 [4].”
From Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor (2022) · cites this paper as [4]
Experimental — accuracy not yet measuredIn the citing paper
“Although two small molecules, AMG510 and MRTX849, which target KRAS G12C have entered clinical trials, these inhibitors produced less profound activity in CRC than non-small cell lung cancer patients [6–10].”
From Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer (2022) · cites this paper as [10]
In the citing paper
“Adagrasib is a selective, irreversible inhibitor of KRASG12C and has favorable properties, including long half-life (23 hours), dose-dependent pharmacokinetics, and central nervous system penetration (3–5).”
From Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRAS G12C-Mutated Metastatic Colorectal Cancer (2024) · cites this paper as [3]
In the citing paper
“Adagrasib is a selective, irreversible inhibitor of KRASG12C and has favorable properties, including long half-life (23 hours), dose-dependent pharmacokinetics, and central nervous system penetration (3–5).”
From Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRAS G12C-Mutated Metastatic Colorectal Cancer (2024) · cites this paper as [3]
In the citing paper
“Adagrasib is a selective, irreversible inhibitor of KRASG12C and has favorable properties, including long half-life (23 hours), dose-dependent pharmacokinetics, and central nervous system penetration (3–5).”
From Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRAS G12C-Mutated Metastatic Colorectal Cancer (2024) · cites this paper as [3]
In the citing paper
“Adagrasib is a selective, irreversible inhibitor of KRASG12C and has favorable properties, including long half-life (23 hours), dose-dependent pharmacokinetics, and central nervous system penetration (3–5).”
From Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRAS G12C-Mutated Metastatic Colorectal Cancer (2024) · cites this paper as [3]
In the citing paper
“AMG-510 and MRTX849 are structural derivatives of ARS-1620 with improved sensitivity of K-RasG12C recognition.”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [7]
In the citing paper
“Another major determinant of KRASG12C inhibitor resistance is the reactivation of upstream tyrosine kinase signaling that promotes SOS1-dependent GTP loading on RAS family members (19, 38, 44, 48–50).”
In the citing paper
“Results from early-stage clinical trials indicate that many cancer patients in this subgroup could significantly benefit from these novel therapeutics.6,7”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [7]
In the citing paper
“In addition, the in vivo responses to MRTX849 in 25 KRASG12C mutant human cell line-derived xenografts were individually represented as sensitive, partially sensitive, or refractory.7”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [7]
In the citing paper
“Instead, K-RasG12C inhibitors act primarily through targeting MAPK/ERK pathway for growth inhibition.4, 5, 6, 7,49”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [7]
In the citing paper
“These preclinical findings strongly imply that intrinsic resistance might be accountable for the heterogeneous responses to K-RasG12C inhibition in the clinic.4, 5, 6, 7,49”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [7]
In the citing paper
“Although long-term efficacy of K-RasG12C-targeted therapies in patients is still unknown,6,50 adaptive resistance to both AMG-510 and MRTX849 has been observed in preclinical animal models.7,11”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [7]
In the citing paper
“In most KRASG12C mutant models, the phosphorylation status of AKT and mTORC1-effector ribosomal protein S6 is barely affected by K-RasG12C inhibition.6,7,12,49”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [7]
In the citing paper
“In another study, the combination of MRTX849 and RMC-4550, a more clinically relevant SHP2 inhibitor, was found to further inhibit K-Ras signaling and exhibit increased antitumor responses in MRTX849-sensitive and -refractory models.7”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [7]
In the citing paper
“although individual genetic alterations, including TP53 (tumor protein p53), CDKN2A (cyclin-dependent kinase inhibitor 2A), STK11 (serine/threonine kinase 11), and KRAS mutant allele frequency failed to predict adaptive resistance.6,7,11”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [7]
In the citing paper
“For example, the expression of select HER (human epidermal growth factor receptor) family members of RTKs and genes controlling early cell-cycle transition exhibited a correlation with the degree of therapeutic response to MRTX849,7”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [7]
In the citing paper
“Furthermore, co-targeting K-RasG12C with PI3K effectors, such as ATK and mTOR has also been shown to be effective in a series of preclinical studies.6,7,10,15,49”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [7]
In the citing paper
“Although no individual genetic alteration at baseline seems to correlate with the therapeutic efficacy of K-RasG12C inhibitors, pre-existing clustered genetic variations, including the overexpression of selected HER family genes could provide some clues on the therapeutic response to MRTX849.7”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [7]
In the citing paper
“Similarly, co-treatment of MRTX849 with palbociclib, a recently FDA-approved CDK4/6 inhibitor, induced more comprehensive tumor regression in several MRTX849-refractory models by profoundly suppressing the retinoblastoma protein (Rb)/E2F transcription factor (E2F) pathway.7”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [7]
In the citing paper
“Although no individual genetic alteration at baseline seems to correlate with the therapeutic efficacy of K-RasG12C inhibitors, pre-existing clustered genetic variations, including the overexpression of selected HER family genes could provide some clues on the therapeutic response to MRTX849.7”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [7]
In the citing paper
“improvements in drug design have culminated in the development of inhibitors that are selective for mutant KRAS in its active or inactive state.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [68]
In the citing paper
“In xenografts and preclinical models, a precursor tool compound MRTX1257 showed promising results, leading to development of MRTX84918,19.”
From Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes (2021) · cites this paper as [19]
In the citing paper
“Possible escape mechanisms for the tumor were identified through in vitro and in vivo models and CRISPR screens and included HER family receptor tyrosine kinases, EGFR, SHP2, and mTOR/S6 pathways19.”
From Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes (2021) · cites this paper as [19]
In the citing paper
“Each tested combination proved to significantly enhance anti-tumor activity of adagrasib compared to any individual therapy alone19.”
From Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes (2021) · cites this paper as [19]
In the citing paper
“When achieving maximal response from adagrasib, association was seen with ERK activity inhibition.”
From Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes (2021) · cites this paper as [19]
In the citing paper
“Using the His-95 groove as an additional binding site, AMG-510 and MRTX849 were the first KRAS G12C inhibitors that were introduced in clinic [71, 91, 92].”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [91]
In the citing paper
“Recent reports (and our unpublished observations; see Results) show that KRASG12C mutant cancer cell lines treated with G12C-Is also develop adaptive resistance (Hallin et al., 2020; Lou et al., 2019; Misale et al., 2019; Ryan et al., 2020; Xue et al., 2020).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Hallin et al., 2020
In the citing paper
“G12C inhibitors (G12C-Is) have significant but limited efficacy in KRAS-mutant malignancies, mostly due to “adaptive resistance.””
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Hallin et al., 2020
In the citing paper
“Covalent cross-linking to codon 12 cysteine leads to an induced fit of the inhibitor in KRASG12C and trap the protein in its inactive, GDP-bound state (20–23).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [23]
In the citing paper
“These studies reported that adaptive response to G12C-Is could be minimized by combining G12C-I with RTK or SHP2-Is (Hallin et al., 2020; Lou et al., 2019; Ryan et al., 2020; Xue et al., 2020).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Hallin et al., 2020
In the citing paper
“In early clinical studies, they have demonstrated promising activity in patients whose tumors harbor KRASG12C mutation (23, 24).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [23]
In the citing paper
“In preclinical studies, KRASG12C inhibitors have demonstrated significant and selective in vitro toxicity in KRASG12C mutant cancer cells; and these inhibitors are effective at inhibiting the growth of KRASG12C mutant xenograft and PDX tumors in mice (21–23).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [23]
In the citing paper
“These experiments have identified receptor tyrosine kinase (RTK) signaling to PI3K and mTOR (23, 37–40), as well as the autophagy pathway (30) as collateral dependencies with KRAS and MAPK pathway inhibitors.”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [23]
In the citing paper
“Two KRASG12C inhibitors, sotorasib (AMG510) and adagrasib (MRTX849) have entered clinical development and they have demonstrated promising activities in solid tumors with KRASG12C mutation, particularly among patients with KRASG12C non-small cell lung cancer (23, 24).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [23]
In the citing paper
“Clinically active, covalent KRASG12C inhibitors have provided the first opportunity to directly target this key oncoprotein (Canon et al., 2019; Hallin et al., 2020; Stephen et al., 2014).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Hallin et al., 2020
In the citing paper
“initial reports from phase I trials show tumor responses in KRASG12C tumors are partial and restricted to a subset of patients (Canon et al., 2019; Hallin et al., 2020).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Hallin et al., 2020
In the citing paper
“ARS is less potent than other G12C-Is, such as AMG-510 and MRTX1257 (Canon et al., 2019; Hallin et al., 2020).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Hallin et al., 2020
In the citing paper
“MRTX849 (adagrasib) developed by Mirati Therapeutics, has been identified as a highly selective covalent inhibitor of KRAS (G12C) and is currently in phase I/II clinical studies [44, 45].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [44]
In the citing paper
“In KRAS (G12C) positive cell lines and patient-derived xenograft models from multiple tumor types, 65% of the models showed significant tumor regression (Table 1) [60].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [60]
In the citing paper
“Hallin et al. illustrated that genetic alterations in cell cycle regulators resulted in cell cycle dysregulation and changed KRAS mutant allele frequency, identifying additional factors that could attenuate the therapeutic response to MRTX849 [60].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [60]
In the citing paper
“Inhibition of cell cycle genes in vivo in MRTX849-treated xenografts intensified further tumor growth inhibition over the effects of KRAS inhibition alone [60].”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [60]
In the citing paper
“It was found that up to 20% of KRAS-mutant NSCLC has concurrent CDKN2A mutations.”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [60]
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“In agreement with prior KRASG12C inhibitor studies (5), MRTX849 demonstrated improved potency in the 3-D assay format, as all but one KRASG12C-mutant cell line exhibited an IC50 value below 100 nmol/L.”
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“The differential response to KRAS G12C inhibitors were demonstrated by many preclinical studies on KRAS G12C ‐ mutant CRC and NSCLC cell lines and tumor models [24, 25, 36, 52].”
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Metadata
- Authors
- Hallin, J., Engstrom, L. D., Hargis, L., Calinisan, A., Aranda, R., Briere, D. M., Sudhakar, N., Bowcut, V., Baer, B. R., Ballard, J. A., Burkard, M. R., Fell, J. B., Fischer, J. P., Vigers, G. P., Xue, Y., Gatto, S., Fernandez-Banet, J., Pavlicek, A., Velastagui, K., Chao, R. C., Barton, J., Pierobon, M., Baldelli, E., Patricoin, E. F., Cassidy, D. P., Marx, M. A., Rybkin, I. I., Johnson, M. L., Ou, S.-H. I., Lito, P., Papadopoulos, K. P., Jänne, P. A., Olson, P., & Christensen, J. G.
- Affiliations
- Mirati Therapeutics (United States) (US)
- Array BioPharma (United States) (US)
- 3Memorial Sloan Kettering Cancer Center, New York, New York.
- 4Monoceros Biosystems LLC, San Diego, California.
- George Mason University (US)
- Dana-Farber Cancer Institute (US)
- Henry Ford Hospital (US)
- Tennessee Oncology (US)
- University of California, Irvine (US)
- Memorial Sloan Kettering Cancer Center (US)
- South Texas Accelerated Research Therapeutics (US)
- 6Dana-Farber Cancer Institute, Boston, Massachusetts.
- Corresponding author
- Christensen, James G.
- ORCID
- Hallin, Jill
- Engstrom, Lars D.
- Hargis, Lauren
- Calinisan, Andrew
- Aranda, Ruth
- Briere, David M.
- Sudhakar, Niranjan
- Bowcut, Vickie
- Baer, Brian R.
- Fell, Jay B.
- Vigers, Guy P.
- Xue, Yaohua
- Gatto, Sole
- Fernandez-Banet, Julio
- Chao, Richard C.
- Pierobon, Mariaelena
- Baldelli, Elisa
- Cassidy, Douglas P.
- Marx, Matthew A.
- Rybkin, Igor I.
- Johnson, Melissa L.
- Ou, Sai-Hong Ignatius
- Lito, Piro
- Papadopoulos, Kyriakos P.
- Olson, Peter
- Christensen, James G.
- Venue
- Cancer Discovery
- Published
- 2020-01-01
- Volume
- 10
- Issue
- 1
- Pages
- 54-71
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC6954325
- OpenAlex
- W2982602983
- Semantic Scholar
- ea93072ecabd7f1aff015f255c8e7366c80187c9
- Cited by
- 1,304
- References
- 44
- Citations by year
- 2026: 134 · 2025: 180 · 2024: 189 · 2023: 193 · 2022: 225 · 2021: 234 · 2020: 140
- FWCI
- 50.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH NCI (1R01CA23074501, 1R01CA23026701A1, 1F30CA232549-01)
- 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
- adagrasib, KRAS-mutant cancer, drug resistance mechanisms, receptor tyrosine kinase activation, cell cycle dysregulation, lung adenocarcinoma, colon adenocarcinoma, patient-derived xenografts, pharmacogenomics, pharmacodynamics
- MeSH terms
- Adenocarcinoma of Lung, Acetonitriles, Animals, Antineoplastic Agents, Disease Models, Animal, Female, Humans, Lung Neoplasms, Mice, Inbred BALB C, Mice, Nude, Middle Aged, Mutation, Piperazines, Prognosis, Pyrimidines, Pyrrolidines, Tumor Cells, Cultured, Signal Transduction, Proto-Oncogene Proteins p21(ras), Mice, SCID, Mice, Inbred NOD, Apoptosis, Clinical Trials, Phase I as Topic, Xenograft Model Antitumor Assays, Cell Proliferation, Mice
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