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DRUG:

MRTX1133

i
Other names: MRTX1133, MRTX-1133, MRTX 1133
Company:
BMS
Drug class:
KRAS G12D inhibitor
9d
MGST1 facilitates novel KRASG12D inhibitor resistance in KRASG12D-mutated pancreatic ductal adenocarcinoma by inhibiting ferroptosis. (PubMed, Mol Med)
Our data showed that KRASG12D inhibitor MRTX1133 combined with PKF-118-310 could enhance the effectiveness of MRTX1133 treatment response through induction of ferroptosis via inhibiting MGST1 expression in MRTX1133-resistant PDAC cells and tumors. This evidence may provide a promising strategy to overcome KRASG12D inhibitor MRTX1133 resistance in PDAC patients with KRASG12D mutations.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • TCF4 (Transcription Factor 4)
|
KRAS mutation • KRAS G12D • CTNNB1 expression
|
MRTX1133
28d
Exploration of Cryptic Pockets Using Enhanced Sampling Along Normal Modes: A Case Study of KRAS G12D. (PubMed, J Chem Inf Model)
These methods have been applied as a proof-of-concept to KRAS and have shown they can predict known cryptic binding sites. Furthermore, we performed ligand-binding simulations of a known inhibitor (MRTX1133) to shed light on the nature of cryptic pockets in KRASG12D and the role of conformational selection vs induced-fit mechanism in the formation of these cryptic pockets.
Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation • KRAS G12C • KRAS G12D • KRAS wild-type • RAS wild-type • KRAS G12
|
MRTX1133
28d
Synergistic anti-tumor activity, reduced pERK, and immuno-stimulatory cytokine profiles with 5-FU or ONC212 plus KRAS G12D inhibitor MRTX1133 in CRC and pancreatic cancer cells independent of G12D mutation. (PubMed, Am J Cancer Res)
We investigated cell viability, drug synergies, pERK suppression and cytokine, chemokine or growth factor alterations following treatment with 5-Fluorouracil (5-FU) or ONC212 plus MRTX1133 in 6 human CRC and 4 human pancreatic cancer cell lines. Our studies reveal preclinical activity of MRTX1133 alone or synergies when combined with 5-FU or ONC212 against mCRC and pancreatic cancer cells regardless of KRAS G12D mutation. The results suggest that KRAS G12V and KRAS G13D should be further considered in clinical trials including combination therapies involving MRTX1133 and 5-FU or ONC212.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • TNFA (Tumor Necrosis Factor-Alpha) • CXCL8 (Chemokine (C-X-C motif) ligand 8) • IL18 (Interleukin 18)
|
KRAS mutation • KRAS G12C • KRAS G12D • KRAS G12V • KRAS wild-type • KRAS G13D • RAS wild-type • KRAS G13
|
5-fluorouracil • MRTX1133 • ONC212
1m
Targeting KRAS-mutant pancreatic cancer through simultaneous inhibition of KRAS, MEK, and JAK2. (PubMed, Mol Oncol)
Analyses of sotorasib- and MRTX1133-resistant cells showed that trametinib plus fedratinib reversed the resistance to sotorasib or MRTX1133. These findings suggest that the JAK2-mediated pathway and reactivation of the MAPK pathway may play key roles in resistance to KRAS inhibitors in pancreatic cancers. Accordingly, simultaneous inhibition of KRAS, MEK, and JAK2 could be an innovative therapeutic strategy against KRAS-mutant pancreatic cancer.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • JAK2 (Janus kinase 2)
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KRAS mutation • KRAS G12C • KRAS G12D
|
Mekinist (trametinib) • Lumakras (sotorasib) • MRTX1133 • Inrebic (fedratinib)
2ms
Microsecond Molecular Dynamics Simulation to Gain Insight Into the Binding of MRTX1133 and Trametinib With KRASG12D Mutant Protein for Drug Repurposing. (PubMed, J Mol Recognit)
The machine learning approach reveals that van der Waals interactions among the residues play vital role in complex stability and the potential amino acids involved in drug-receptor interactions of each complex. These details provide a molecular-level understanding of drug binding mechanisms, offering essential knowledge for further drug repurposing and potential drug discovery.
Journal
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KRAS (KRAS proto-oncogene GTPase)
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KRAS mutation • KRAS G12D • KRAS G12
|
Mekinist (trametinib) • MRTX1133
2ms
Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation • KRAS G12D • KRAS G12
|
MRTX1133
2ms
Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
|
MRTX1133
2ms
Macroautophagy/autophagy promotes resistance to KRASG12D-targeted therapy through glutathione synthesis. (PubMed, Cancer Lett)
Consequently, genetic interventions (utilizing ATG5 or BECN1 knockout) or pharmacological inhibition of autophagy (with chloroquine, bafilomycin A1, or spautin-1) enhance the anticancer activity of MRTX1133 in vitro and in various animal models (subcutaneous, patient-derived xenograft, and orthotopic). Moreover, the release of histones by apoptotic cells triggers an adaptive immune response when combining an autophagy inhibitor with MRTX1133 in immunocompetent mice. These findings establish a new strategy to overcome KRASG12D-targeted therapy resistance by inhibiting autophagy-dependent glutathione synthesis.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • ATG5 (Autophagy Related 5) • APAF1 (Apoptotic peptidase activating factor 1) • BECN1 (Beclin 1)
|
KRAS mutation • KRAS G12D • KRAS G12 • MTOR mutation
|
MRTX1133 • chloroquine phosphate
3ms
Targeting BCL2 with Venetoclax Enhances the Efficacy of the KRASG12D Inhibitor MRTX1133 in Pancreatic Cancer. (PubMed, Cancer Res)
Venetoclax could also re-sensitize MRTX1133-resistant PDAC cells to MRTX1133 in 3D cultures, and tumors established from resistant cells responded to the combination of MRTX1133 and venetoclax. These results provide a rationale for the clinical testing of MRTX1133 and venetoclax in PDAC patients.
Journal • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • BCL2 (B-cell CLL/lymphoma 2) • BCL2L11 (BCL2 Like 11)
|
Venclexta (venetoclax) • MRTX1133
4ms
Discovery of Potent and Selective G9a Degraders for the Treatment of Pancreatic Cancer. (PubMed, J Med Chem)
G9D-4 exhibited effective antiproliferative activities in a panel of pancreatic cancer cell lines and was able to sensitize KRASG12D mutant pancreatic cancer cells to KRASG12D inhibitor MRTX1133. These data clearly demonstrated the practicality and importance of a selective G9a degrader as a preliminary chemical probe suitable for understanding G9a-related biology and a promising strategy for the treatment of pancreatic cancer.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • LY9 (Lymphocyte Antigen 9)
|
MRTX1133
4ms
Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer. (PubMed, Cancer Discov)
Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy...Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.
Journal
|
EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • YAP1 (Yes associated protein 1) • CDK6 (Cyclin-dependent kinase 6)
|
Lumakras (sotorasib) • Krazati (adagrasib) • MRTX1133
5ms
Pathways and mechanism of MRTX1133 binding to KRAS G12D elucidated by molecular dynamics simulations and Markov state models. (PubMed, Int J Biol Macromol)
Additionally, 8 key residues that are essential for MRTX1133 recognition and tight binding at the preferred low energy states were identified by MM/GBSA analysis. In sum, this study provides a new perspective on understanding the pathways and mechanism of MRTX1133 binding to KRAS G12D.
Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
MRTX1133
5ms
Inhibition of GTPase KRASG12D: a review of patent literature. (PubMed, Expert Opin Ther Pat)
Since the approval of AMG510 (Sotorasib), there has been an increasing focus on the inhibition of KRASG12D, leading to numerous reports of related inhibitors and degraders. Among them, MRTX1133, as the first KRASG12D inhibitor to enter clinical trials, has demonstrated excellent tumor suppression in various KRASG12D-bearing human tumor xenograft models. It is important to note, however, that understanding the mechanisms of acquired resistance caused by KRAS inhibition and developing additional combination therapies is crucial. Moreover, seeking covalent inhibition of KRASG12D also holds significant potential.
Review • Journal
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KRAS (KRAS proto-oncogene GTPase)
|
Lumakras (sotorasib) • MRTX1133
5ms
Organoids for functional precision medicine in advanced pancreatic cancer. (PubMed, Gastroenterology)
We report the largest prospective study aiming at implementing PDO-based FPM and identify very robust predictive values in this clinical setting. In a clinically relevant turnaround-time, we identify putative hits for 91% of patients, providing unexpected potential survival benefits in this very aggressive indication. While this remains to be confirmed in interventional precision oncology trials, PDO collection already provide powerful opportunities for drugs and combinatorial treatment development.
Journal • Metastases
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KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B)
|
gemcitabine • docetaxel • vinorelbine tartrate • MRTX1133
5ms
Structural perspectives on recent breakthrough efforts toward direct drugging of RAS and acquired resistance. (PubMed, Front Oncol)
Of interest, the non-covalent KRASG12D targeting inhibitor MRTX-1133 has shown promising results in humanized pancreatic cancer mouse models and is seemingly making its way from bench to bedside...Finally, the next generation of KRAS mutant-specific and pan-RAS tri-complex inhibitors have revolutionized RAS drug discovery. This review will give a structural biology perspective on the current generation of KRAS inhibitors through the lens of emerging secondary mutations and acquired resistance.
Preclinical • Review • Journal
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KRAS (KRAS proto-oncogene GTPase)
|
MRTX1133
6ms
In Silico Prediction of New Inhibitors for Kirsten Rat Sarcoma G12D Cancer Drug Target Using Machine Learning-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulation Approaches. (PubMed, Pharmaceuticals (Basel))
Furthermore, to evaluate the stability of the compounds with a good docking score, the top two complexes and the standard complex (MRTX-1133) were subjected to 200 ns MD simulation...Our identified hits have the potential to inhibit the KRAS G12D mutation and can help combat cancer. To the best of our knowledge, this is the first study in which machine-learning-based virtual screening, molecular docking, and molecular dynamics simulation were carried out for the identification of new promising inhibitors for the KRAS G12D mutant.
Preclinical • Journal • Machine learning
|
KRAS (KRAS proto-oncogene GTPase)
|
MRTX1133
6ms
State-of-the-art and upcoming trends in RAS-directed therapies in gastrointestinal malignancies. (PubMed, Curr Opin Oncol)
Targeting RAS has become an important strategy in treating gastrointestinal cancer. These findings in this review underscore the importance of a multidisciplinary approach, integrating advances in molecular profiling, targeted therapy, immunotherapy, and clinical research to optimize treatment strategies for patients with KRAS-mutant gastrointestinal malignancies.
Journal • IO biomarker
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KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
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MRTX1133 • RMC-6236
7ms
Targeting KRAS in pancreatic cancer. (PubMed, Oncol Res)
However, the most common KRAS mutations in PDAC are G12D (44%), G12V (34%) and G12R (20%) that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung cancer...Recently, the KRAS G12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in development. The other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor (GEF) Son of Sevenless 1 that drives KRAS. These agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes.
Review • Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation • KRAS G12C • KRAS G12D • KRAS G12V
|
Lumakras (sotorasib) • Krazati (adagrasib) • MRTX1133
7ms
Site-Specific Mutagenesis Screening in KRASG12D Mutant Library to Uncover Resistance Mechanisms to KRASG12D Inhibitors. (PubMed, Cancer Lett)
We observed that secondary mutations in KRASG12D can lead to acquired resistance to MRTX1133 and BI-2865, a novel pan-KRAS inhibitor, in human cancer cell lines. This evidence is critical for devising new strategies to counteract resistance mechanisms and, ultimately, enhance treatment outcomes in patients with KRASG12D-mutant cancers.
Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation • KRAS G12D • KRAS G12D + KRAS G12V • KRAS Q99L
|
MRTX1133
8ms
Gluing GAP to RAS Mutants: A New Approach to an Old Problem in Cancer Drug Development. (PubMed, Int J Mol Sci)
As a proof of concept, we identify two new, drug-like small molecules with the new method; these compounds specifically inhibit the growth of the PANC-1 cell line with KRAS mutation G12D in vitro and in vivo. Importantly, the two new compounds show significantly lower IC50 and higher specificity against the G12D KRAS mutant human pancreatic cancer cell line PANC-1, as compared to the recently described selective G12D KRAS inhibitor MRTX-1133.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • RAS (Rat Sarcoma Virus)
|
KRAS mutation • KRAS G12D • RAS mutation • KRAS G12
|
MRTX1133
10ms
The extracellular niche and tumor microenvironment enhance KRAS inhibitor efficacy in pancreatic cancer. (PubMed, Cancer Res)
Further investigation of the immunological response using single-cell sequencing and multispectral imaging revealed that tumor regression was associated with suppression of neutrophils and influx of effector CD8+ T cells. Together, these findings demonstrate that both tumor cell-intrinsic and extrinsic events contribute to response to MRTX1133 and credential KRASG12D inhibition as a promising therapeutic strategy for a large percentage of PDAC patients.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • ITGB1 (Integrin Subunit Beta 1) • TAFAZZIN (Tafazzin)
|
KRAS G12D
|
MRTX1133
10ms
Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS. (PubMed, J Med Chem)
Herein, we report the design, synthesis, and biological evaluation of a series of KRAS PROTACs by connecting the analogues of MRTX1133 and the VHL ligand...This compound selectively and potently suppressed the growth of multiple KRAS mutant cancer cells, displayed favorable pharmacokinetic and pharmacodynamic properties in mice, and showed significant antitumor efficacy in the AsPC-1 xenograft mouse model. Further optimization of 8o appears to be promising for the development of a new chemotherapy for KRAS-driven cancers as the complementary therapeutic strategy to KRAS inhibition.
Journal
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KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
|
MRTX1133
11ms
Antitumor effect of a small-molecule inhibitor of KRAS in xenograft models of mucinous appendicular neoplasms. (PubMed, Exp Hematol Oncol)
The results obtained in this work showed a profound inhibition of tumor growth, which was associated with a reduction in cell proliferation, an increase in apoptosis, and a reduction in the MAPK and PI3K/AKT/mTOR signaling pathways. In conclusion, these results demonstrate the high potency and efficacy of MRTX1133 in KRAS-PMP tumors and provide a rationale for clinical trials.
Preclinical • Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
|
MRTX1133
12ms
Metabolomic, Proteomic, and Single-Cell Proteomic Analysis of Cancer Cells Treated with the KRAS Inhibitor MRTX1133. (PubMed, J Proteome Res)
At 48 h of treatment, two distinct populations of cells can be observed based on the level of effectiveness of the drug in decreasing the total abundance of the KRAS protein in each respective cell, with results that are effectively masked in the bulk cell analysis. All mass spectrometry data and processed results are publicly available at www.massive.ucsd.edu at accessions PXD039597, PXD039601, and PXD039600.
Journal • Metabolomic study
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KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
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MRTX1133
12ms
Design, Synthesis, and Pharmacological Evaluation of Multisubstituted Pyrido[4,3-d]pyrimidine Analogues Bearing Deuterated Methylene Linkers as Potent KRAS Inhibitors. (PubMed, J Med Chem)
These new inhibitors were found to have dose-dependent anti-tumor efficacy in the AsPC-1 xenograft mouse models with a tumor growth inhibition of approximately 70% at a dose of 20 mg/kg twice daily (i.p.). Despite the non-optimal pharmacokinetic properties similar to those of MRTX1133, the high in vitro and in vivo potency of these new inhibitors call for further profiling.
Journal
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KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
|
MRTX1133
1year
A small molecule with big impact: MRTX1133 targets the KRASG12D mutation in pancreatic cancer. (PubMed, Clin Cancer Res)
The recent approval of sotorasib (AMG510), a small-molecule, covalent, and selective KRASG12C inhibitor, for treating patients with non-small cell lung cancer represents a breakthrough in KRAS targeted therapy. Additionally, we discuss potential challenges and future directions for MRTX1133 therapy for PDAC, including overcoming intrinsic and acquired drug resistance, developing effective combination therapies, and improving MRTX1133's oral bioavailability and target spectrum. The promising results obtained from preclinical studies suggest that MRTX1133 could revolutionize the treatment of PDAC, bring about a paradigm shift in its management.
Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation • KRAS G12D • KRAS G12V • KRAS G12
|
Lumakras (sotorasib) • MRTX1133
1year
Cetuximab Enhances the Efficacy of MRTX1133, a Novel KRAS Inhibitor, in Colorectal Cancer Treatment. (PubMed, Anticancer Res)
The combination of MRTX1133 and cetuximab serves as a potential and promising therapeutic approach for colorectal cancer with KRAS mutation. KRAS is a frequent genetic mutation not only in colorectal cancer, but also in pancreatic and lung cancer, and the results of this study open new avenues for potential treatment of many cancer patients.
Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation • KRAS wild-type • RAS wild-type
|
Erbitux (cetuximab) • MRTX1133
1year
Dual inhibition of KRASG12D and pan-ERBB is synergistic in pancreatic ductal adenocarcinoma. (PubMed, Cancer Res)
Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer.
Journal
|
EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation • KRAS G12D • KRAS G12
|
Gilotrif (afatinib) • MRTX1133
1year
KRAS inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8 T cells. (PubMed, Cancer Cell)
Mechanistically, inhibition of KRAS in advanced PDAC and human patient derived organoids induces FAS expression in cancer cells and facilitates CD8 T cell-mediated death. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with ICB in clinical trials.
Journal • Metastases
|
KRAS (KRAS proto-oncogene GTPase) • CD8 (cluster of differentiation 8)
|
KRAS mutation
|
MRTX1133
1year
Mutant-specific pharmacological inhibition of KRAS in multiple myeloma and functional genomics studies to identify mechanisms regulating myeloma cell response vs. resistance to KRAS inhibition. (IMW 2023)
MRTX1257 predominantly reduced proliferation of XG7 cells, whereas MRTX1133 led to potent cell death induction of KARPAS620 and KP6 cells. Combinations of MRTX1257 with investigational or established anti-MM drugs, including melphalan, bortezomib or pomalidomide, led to no antagonism and in some cases – including combination with MEKi trametinib – caused supra-additive effects... This study documents mutant-specific activity of KRAS G12C and G12D inhibitors in MM cells and provides functional insights into the pharmacological inhibition of KRAS in MM. Ongoing in vitro and in vivo studies are examining the targeting of genes/pathways associated with escape from KRAS inhibition, as a framework for future efforts to improve the rates, depth and durability of responses to KRAS inhibition in MM.
Genomic study
|
EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • ETV5 (ETS Variant Transcription Factor 5) • DUSP6 (Dual specificity phosphatase 6) • ETV4 (ETS Variant Transcription Factor 4)
|
KRAS mutation • KRAS G12C • KRAS G12D • RAS mutation
|
Mekinist (trametinib) • bortezomib • pomalidomide • melphalan • MRTX1133 • MRTX1257
over1year
Targeting KRAS in pancreatic cancer: Emerging therapeutic strategies. (PubMed, Adv Cancer Res)
The inhibitors targeting G12D mutation (such as MRTX1133) have been recently developed, whereas those targeting other mutations are still lacking...In addition, we recently demonstrated that the combination of sotorasib with DT2216 (a BCL-X-selective degrader) synergistically inhibits G12C-mutated pancreatic cancer cell growth in vitro and in vivo...This chapter will review KRAS biochemistry, signaling pathways, different mutations, emerging KRAS-targeted therapies, and combination strategies. Finally, we discuss challenges associated with KRAS targeting and future directions, emphasizing pancreatic cancer.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • BCL2L1 (BCL2-like 1)
|
KRAS mutation • KRAS G12D • KRAS G12V • KRAS G12
|
Lumakras (sotorasib) • MRTX1133 • DT2216
over1year
Feedback activation of EGFR/wild-type RAS signaling axis limits KRAS inhibitor efficacy in KRAS-mutated colorectal cancer. (PubMed, Oncogene)
Blockade of activated EGFR with clinically used antibodies or kinase inhibitors suppressed the EGFR/wild-type RAS signaling axis, sensitized MRTX1133 monotherapy, and caused the regression of KRAS-mutant CRC organoids and cell line-derived xenografts. Overall, this study uncovers feedback activation of EGFR as a prominent molecular event that restricts KRAS inhibitor efficacy and establishes a potential combination therapy consisting of KRAS and EGFR inhibitors for patients with KRAS-mutated CRC.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • ERRFI1 (ERBB Receptor Feedback Inhibitor 1)
|
KRAS mutation • EGFR mutation • EGFR wild-type • RAS wild-type
|
MRTX1133
over1year
Combination of 5-FU plus KRAS G12D inhibitor MRTX1133 against human colorectal and pancreatic cancer cells and the affects on inhibition of pERK and immune-stimulatory cytokine patterns in in KRAS G12D and KRAS G12V tumor cells. (ASCO 2023)
Our studies reveal strong synergy between MRTX1133 & 5-FU in human pancreatic & colon cancer models at much lower than IC50 dosage which is important for avoiding side effects. This is the first description that effect of KRAS G12D inhibitor MRTX1133 is active on KRAS G12V. The surprising synergy in KRAS G12V samples with combination therapy and the important synergistic change in cytokine patterns suggests potential strong immune stimulatory anti-cancer effects of MRTX1133 & 5FU against mCRC and pancreatic cancer cells regardless of KRAS G12D mutation which should be considered when including patients with respective mutations in clinical trials.
Tumor cell
|
KRAS (KRAS proto-oncogene GTPase) • TNFA (Tumor Necrosis Factor-Alpha) • CXCL8 (Chemokine (C-X-C motif) ligand 8) • IL18 (Interleukin 18)
|
KRAS mutation • KRAS G12D • KRAS G12V • KRAS G13
|
5-fluorouracil • MRTX1133
over1year
Immune mechanisms underlie full therapeutic efficacy of a novel inhibitor of KrasG12D in mouse models of pancreatic ductal adenocarcinoma (AACR 2023)
Additionally, more CD8+ T cells in the tumor-draining lymph nodes of MRTX1133-treated mice were IFNγ+ (P < 0.001), illustrating a systemic immune effect from MRTX1133. Our findings indicate that T cells play an important role in MRTX1133’s demonstrated efficacy, suggesting a “vaccine effect” from mutant KRAS inhibition and offering a rationale for testing novel combinations of mutant KRAS inhibitors with cancer immunotherapies.
Preclinical • IO biomarker
|
KRAS (KRAS proto-oncogene GTPase) • CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • CD4 (CD4 Molecule) • GZMB (Granzyme B)
|
KRAS mutation • KRAS G12D • KRAS G12
|
MRTX1133
over1year
Study of MRTX1133 in Patients With Advanced Solid Tumors Harboring a KRAS G12D Mutation (clinicaltrials.gov)
P1/2, N=304, Recruiting, Mirati Therapeutics Inc. | Not yet recruiting --> Recruiting
Enrollment open
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation • KRAS G12D • KRAS G12
|
MRTX1133
over1year
New P1/2 trial • Metastases
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation • KRAS G12D • KRAS G12
|
MRTX1133