MRTX1133

ADT-1004 has strong antitumor activity in aggressive and clinically relevant PDAC models with unique selectivity to block RAS-mediated signaling in RAS mutant cells. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC.

Furthermore, markedly stronger, synergistic antitumor effects were observed upon concomitant treatment with BI-3406 and MRTX1133 in the same in vivo LUAD mouse model. Our data confirm SOS1 as an actionable therapy target in RAS-dependent cancers and suggest that BI-3406 treatment may yield clinical benefit both as monotherapy or as a potential combination partner for multiple RAS-targeting strategies.

This system enhances the efficacy of PGG and MRTX1133, achieving durable remissions (85% overall response rate) and long-term survival (100% progression-free survival) in patient-derived xenografts and spontaneous PDAC mice. This study reveals the role of KRASG12D-preferred PPP reprogramming in MRTX1133 resistance and proposes a potentially therapeutic strategy for KRASG12D-mutated PDAC.

MRTX1133 is a highly selective and first-in-class KRAS-G12D inhibitor under clinical development...This combination therapy also induces high-mobility group box 1 (HMGB1) release, resulting in a subsequent antitumor CD8+ T cell response in immunocompetent mice. Collectively, the study findings underscore the potential to enhance the efficacy of KRAS-G12D blockade therapy by targeting AGER-dependent macropinocytosis.

Furthermore, KRASG12D-containing CAFs were observed to promote tumor chemoresistance to gemcitabine treatment both in vitro and in vivo. Application of a KRAS mutation-specific inhibitor, MRTX1133, has been demonstrated to reverse chemoresistance in PDAC. Moreover, clinical data suggest that patients with KRAS mutations have poorer prognosis following adjuvant chemotherapy. These findings elucidate the mechanism by which oncogenic KRAS mutations promote cancer chemoresistance and remodel tumor environment in a non-autonomous manner, suggesting a novel strategy for targeting KRAS mutations to enhance chemosensitivity in PDAC.

Importantly, cells in which recombination has successfully occurred can be visualized and isolated using the fluorescence emitted by tdTomato. Furthermore, we show that KRASG12D production enables intestinal organoid growth independent of epidermal growth factor (EGF) signaling and that the KRASG12D function is effectively suppressed by specific inhibitor MRTX1133.

P1, N=386, Active, not recruiting, Mirati Therapeutics Inc. | Phase classification: P1/2 --> P1

The study showed that AMG-510 binding significantly stabilizes the amino acids surrounding it, surpassing that of MRTX1133. The insights gained in the present study is expected to be useful in the design and development of new KRAS-targeted drugs.

Although we have shown that the 3D environment dramatically sensitizes cells to MRTX1133 treatment, the synergistic effect of this drug combination is present in both 2D and 3D in the PANC1 pancreatic adenocarcinoma model, which showed high resistance to MRTX1133 in 2D. The effects of the combination treatment show an association with the inhibition of farnesylated regulatory proteins, including HRAS and RHEB, along with the expression level of KRAS. Our study warrants further investigation for the potential applicability of KRAS G12D inhibitors in combination with farnesyl-transferase inhibitors for the treatment of KRAS mutant pancreatic adenocarcinoma.

P1/2, N=386, Active, not recruiting, Mirati Therapeutics Inc. | Recruiting --> Active, not recruiting

We elucidated the mechanism of action of a potent KRAS G12D inhibitor, MRTX1133. Binding of this inhibitor to the switch-2 pocket causes a complete shift of KRAS G12D towards the "inactive" conformation and prevents binding of effector RAS-binding domain (RBD) at physiological concentrations, by signaling through an allosteric network.

Our study provides novel insights into the therapeutic potential of MRTX1133 in treating KRASG12D-mutated CRC by identifying a METTL14/LINC02159/FOXC2 signalling axis that mediates drug response. Our findings highlight the importance of understanding the molecular mechanisms of lncRNAs in cancer to develop effective targeted therapies.

We tested this hypothesis in multiple preclinical PDAC models receiving MRTX1133, an investigational new drug specific for KRAS G12D mutation...Our data demonstrate the abilities of DWI, DCE and MTR derived imaging markers to detect the early (48h) cell death, pronounced stromal changes and development of resistance to KRASi. This study has high translational relevance by testing clinically ready MRI methods, an IND and a genetic engineered mouse model that recapitulates saline features of human PDAC.

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.

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.

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.

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.

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.

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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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.