MRTX1133 / BMS - LARVOL DELTA

Uncovering resistance mechanisms and vulnerabilities of KEAP1 mutated lung adenocarcinoma (ESMO 2024) - "Taken together these findings will contribute to the understanding of resistance mechanisms and will give us insights of therapeutic strategies to determine the best-individualized treatments."

IO biomarker • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KEAP1 • KRAS • NQO1

Therapeutic effects of MRTX1133 in KRAS G12D mutant appendiceal cancer: Insights from organoid and in vivo studies (ESMO 2024) - "To our knowledge, this is the first report of activity of a KRAS inhibitor in pre-clinical models of AA. AA Models with KRASG12D were highly sensitive to MRTX1133 monotherapy providing a clear rationale for clinical testing. However, the presence of GNASR201C appears to cause resistance, suggesting a combination strategy may be required in KRASG12D/GNASmut tumors."

Preclinical • Appendix Cancer • Colon Cancer • Colorectal Cancer • Oncology • Pancreatic Cancer • GNAS • KRAS

Assessment of novel therapeutic treatments in KRAS mutant colorectal cancer using patient-derived organoids (ECP 2024) - "Conclusion The novel KRASG12D inhibitor MRTX1133 showed an effective IC50 20 times lower (nM) in KRASG12D PDO than in LS-174 cells suggesting PDOS as better model for drug testing. As following step, we plan to validate these data by using scRNA-seq, proteomic analysis and 4i to deepen the KRASG12D in CRC."

Clinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS • SMAD2 • TP53

Chemical development in pharmaceutical industry-Technology and innovation (ACS-Fall 2024) - "It serves to develop practical synthetic routes for making drug substances (API) at various stages of the drug development and to ultimately develop feasible chemical processes to support commercial launch of the drugs. In this lecture, the chemical development of selected drugs: adagrasib (MRTX849), MRTX1719, MRTX1133 featuring asymmetric synthesis, flow chemistry via dynamic kinetic resolution, process optimization and manufacturing will be presented."

Targeting BCL2 with Venetoclax Enhances the Efficacy of the KRASG12D Inhibitor MRTX1133 in Pancreatic Cancer (Cancer Res) - "Consistently, BIM was induced in tumors treated with MRTX1133, and venetoclax enhanced the efficacy of MRTX1133 in vivo. 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."

Preclinical • Pancreatic Cancer

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."

IO biomarker • Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BCL2 • BCL2L11 • KRAS

Understanding the effects of mutations and inhibitor binding in KRAS mutation dynamics (ACS-Fall 2024) - "The study found that AMG510-bound KRAS-G12C showed greater energy changes in S-II residues compared to inhibitor-free KRASG12C. The research findings indicate that AMG510 binding significantly stabilizes the surrounding amino acids, outperforming MRTX1133 in this regard."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

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 • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • KRAS • LY9

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 • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CDK6 • EGFR • KRAS • PIK3CA • YAP1

The On-Target MRTX1133 Resistance Mutation KRAS(R68S) Acts by Enhancing Lung Adenocarcinoma Cell Fitness (LUNG-SPORE 2024) - "This biologic activity of a drug resistance mutation thus has major potential implications for the development of future strategies to combat drug resistance mechanisms in KRAS G12D-driven cancers, including lung cancers. (SPORE P50 CA070907)."

Colorectal Cancer • Hepatology • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • AVEN • KRAS

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 • Oncology • KRAS

Kras G12D Inhibition Causes Tumor Regression And Synergizes with Immune Checkpoint Blockade in Immunogenic Lung Cancer Models (LUNG-SPORE 2024) - "Notably, the response to MRTX1133 was durable in autochthonous models...We also evaluated the efficacy of G12D inhibitor in the newly developed Genetically engineered mouse lung model derived syngeneic lung cancer models with high tumor mutational burden (TMB). In summary, our research sheds light on the promise of the G12D inhibitor in treating established GEMM tumors and sheds light into novel immune-mediated biology associated with Kras G12D inhibition."

Checkpoint block • Checkpoint inhibition • Preclinical • Tumor mutational burden • Lung Cancer • Oncology • Solid Tumor • CD8 • KRAS • TMB

Identifying Resistant Mechanisms To Direct KRAS-Inhibitors (LUNG-SPORE 2024) - "Recent breakthroughs, however, have resulted in the development of covalent inhibitors capable of selectively targeting the KRAS G12C mutation, like Sotorasib (AMG510) and Adagrasib (MRTX849) which are approved by the FDA due to their encouraging effects in clinical trials. The identification of selective inhibitors of other oncogenic KRAS alleles, such as the noncovalent KRAS-G12D inhibitor, MRTX1133, and a pan-KRAS-inhibitor drug, BI3706674 is also a promising next step in the treatment of KRAS-dependent malignancies...We are currently performing in vitro and In vivo studies to understand the therapeutic efficacy of a TEAD inhibitor (VT107) in combination with KRASi (MRTX849 or MRTX1133) to either reverse or prevent resistance to the direct KRAS inhibitors. Successful completion of this research will help address the urgent need to understand ways to overcome resistance to KRAS inhibitors and increase their clinical efficacy."

Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS • TEAD1 • YAP1

Gene expression correlates of adagrasib response in KRAS G12C mutated non-small cell lung cancer (NSCLC). (ASCO 2024) - "Background: KRAS G12C inhibitors such as adagrasib and sotorasib have shown clinical promise in targeting KRAS G12C -mutated lung cancers; however, most patients develop primary or secondary resistance...Studies of Lkb1-deficient KRAS G12C and Kras G12D lung cancer mouse models and organoids, treated with KRAS inhibitors adagrasib and MRTX1133, respectively, reveal that tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition...KRAS G12C mutated lung adenocarcinoma patients with a higher expression of squamous cell carcinoma gene expression signature respond poorly to adagrasib treatment. Expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • KRAS • KRT6A • STK11 • TP63

[PREPRINT] Drug combinations with apoptosis pathway targeted agents alrizomadlin, pelcitoclax, and dasminapant in multi-cell type tumor spheroids (bioRxiv) - "The malignant cell lines were derived from a range of solid tumors including uterine carcinosarcoma, synovial sarcoma, rhabdomyosarcoma, soft tissue sarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor (MPNST), pancreas, ovary, colon, breast, and small cell lung cancer. Interactions were observed from combinations of the apoptosis pathway targeted agents. Additionally, interactions were observed from combinations of the apoptosis pathway targeted agents with other agents, including PARP inhibitors, the XPO1 inhibitor eltanexor, and the PI3K inhibitor copanlisib. Enhanced activity was also observed from combinations of the apoptosis pathway targeted agents with MAPK pathway targeted agents, including the MEK inhibitor cobimetinib as well as adagrasib and MRTX1133, which specifically target the KRAS G12C and G12D variants, respectively."

Preclinical • Preprint • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Lung Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Rhabdomyosarcoma • Small Cell Lung Cancer • Soft Tissue Sarcoma • Solid Tumor • Synovial Sarcoma • Uterine Cancer

Assessment of novel therapeutic treatments in KRAS mutant Colorectal Cancer using Patient-Derived Organoids (EACR 2024) - "Interestingly, the novel KRASG12D inhibitor MRTX1133 showed an effective EC50 20 times lower (50 nM) in KRASG12D PDO compared to that in LS-174T cells (1 uM)...The variation in drug responses in the same KRAS status might be possibly explained by the coexistence of different patient-specific tumor cell clones in the CRC PDOs, that ultimately affect the overall CRC PDOs behavior.Conclusion Our preliminary data greatly support PDOs as a more reliable platform to explore new therapeutic strategies in CRC, since they maintain the patient inter/intra-tumor heterogeneity. Next, we plan to integrate our data with omics profiling and single-cell resolved multiplexed protein readout to deepen our understanding in KRAS perturbed signaling network following targeted drug treatment in CRC."

Clinical • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS • SMAD2 • TP53

SOS1 inhibitor BI-3406 demonstrates anti-tumor activity akin to SOS1 genetic ablation in KRASG12D mutant tumors (EACR 2024) - "Moreover, in KRASG12D allografts genetic and pharmacological inhibition of SOS1 displayed anti-tumor efficacy comparable to treatment with a KRASG12D inhibitor MRTX1133 and resulted in synergistic antitumor effect when both inhibitors were combined. Furthermore, consistent with previous genetic evidence from our laboratory, in vivo administration of BI-3406 in an immunocompetent mouse model of KRASG12D-driven lung cancer resulted in a strong reduction of lung tumor burden and significant downmodulation of the pro-tumorigenic tumor microenvironment (TME). Conclusion Our data confirm the SOS GEFs as bona fide therapeutic targets in RAS-dependent cancers and identify a therapeutic window for SOS1 pharmacological inhibition that may translate to clinical benefits through reduction of intrinsic tumor burden and impairment of extrinsic pro-tumorigenic contributions of the surrounding TME."

Lung Cancer • Oncology • Solid Tumor • KRAS

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."

Journal • Review • Oncology • KRAS

Preclinical characterization of HBW-012-E, a novel, potent, selective, safe, and orally active KRAS G12D inhibitor with superior pharmacokinetic (PK) properties and anti-tumor efficacy. (ASCO 2024) - "A new KRAS G12D inhibitor, HBW-012-E, was identified. Its preclinical profile, including potency, efficacy, and PK properties, are all superior to MRTX1133, and its safety meets the criteria of clinical development. It can potentially be used to treat intractable tumors mediated by KRAS G12D mutations, such as pancreatic cancer that still lacks effective treatments."

PK/PD data • Preclinical • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

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 • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CDKN2A • CDKN2B • KRAS • TP53

Synergistic inhibition of CXCL8 following MRTX1133 treatment with ONC212 or 5-FU in KRAS G12D and G12V mutant CRC and PDAC cell lines. (ASCO 2024) - "Considering the important role of KRAS mutations and CXCL8 in pathogenesis of CRC & PDAC, the effective inhibition of CXCL8 with the use of targeted therapy in combination could enhance treatment response and patient survival."

Preclinical • Colorectal Cancer • Pancreatic Cancer • CXCL8 • KRAS

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."

Journal • Preclinical • Review • Gastrointestinal Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Sarcoma • Solid Tumor • KRAS

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."

Journal • Machine learning • Preclinical • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Sarcoma • Solid Tumor • KRAS

MICROBIAL METABOLITE UROLITHIN A REDUCES INFLAMMATION AND ENHANCES GUT BARRIER FUNCTION IN KRASG12D INHIBITOR MRTX1133-TREATED MOUSE MODELS OF PANCREATIC CANCER (DDW 2024) - "Further cytokine array using serum for inflammation markers confirmed the reduced inflammation with addition of Uro A to MRTX1133. In summary our investigations illuminate Uro A's capacity to mitigate drug-induced inflammation and preserve gut barrier integrity and suggesting combination of MRTX1133 and Uro A could be a promising therapeutic approach for PDAC."

Preclinical • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

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."

IO biomarker • Journal • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • Solid Tumor • KRAS