A5008226128- Cancer, Hypoxia, and Metabolism
- Cancer Research and Treatments
- Mechanisms of cancer metastasis
- ATP Synthase and ATPases Research
- Neuroblastoma Research and Treatments
- Biochemical and Molecular Research
- Cancer Immunotherapy and Biomarkers
- Cell death mechanisms and regulation
- Pancreatic and Hepatic Oncology Research
- Protein Degradation and Inhibitors
- Cancer Genomics and Diagnostics
- CAR-T cell therapy research
- Phagocytosis and Immune Regulation
- Signaling Pathways in Disease
- Cancer Mechanisms and Therapy
- Radiopharmaceutical Chemistry and Applications
- Cancer-related Molecular Pathways
- Chemokine receptors and signaling
- Colonialism, slavery, and trade
- Erythrocyte Function and Pathophysiology
- Advanced Breast Cancer Therapies
- Peptidase Inhibition and Analysis
- Global Maritime and Colonial Histories
- Nerve injury and regeneration
- Amino Acid Enzymes and Metabolism
Revolution Medicines (United States)
2023-2025
Neurological Surgery
2021-2022
University of California, San Francisco
2017-2022
UCSF Helen Diller Family Comprehensive Cancer Center
2017-2021
Laboratoire Interdisciplinaire pour la Sociologie Economique
2020
Université Paris-Est Créteil
2020
Université Claude Bernard Lyon 1
2013-2018
Centre National de la Recherche Scientifique
2013-2018
Centre Léon Bérard
2018
Inserm
2013-2018
Abstract RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor the active, GTP-bound state both mutant and wild-type variants canonical RAS isoforms with broad therapeutic potential for aforementioned unmet medical need. exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 KRAS. Notably, oral administration was tolerated in vivo drove profound tumor regressions...
Abstract Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by mutations 1,2 . RMC-7977 is highly selective inhibitor active GTP-bound forms KRAS, HRAS and NRAS, affinity for both mutant wild-type variants 3 More than 90% cases pancreatic ductal adenocarcinoma (PDAC) activating in KRAS 4 Here we assessed therapeutic comprehensive range PDAC models. We observed broad pronounced anti-tumour activity across models...
The pivotal step on the mitochondrial pathway to apoptosis is permeabilization of outer membrane (MOM) by oligomers B-cell lymphoma-2 (Bcl-2) family members Bak or Bax. However, how they disrupt MOM integrity unknown. A longstanding model that activated and Bax insert two α-helices, α5 α6, as a hairpin across MOM, but recent insights oligomer structures question this model. We have clarified these helices contribute perforation determining that, in oligomers, (like α5) remains part protein...
Abstract KRASG12D is the most frequent KRAS mutation in human cancers, with highest prevalence pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC) and non-small cell lung (NSCLC). RMC-9805 a first-in-class, oral, mutant-selective covalent inhibitor of GTP-bound active RAS(ON) form KRASG12D. The formation stable, high affinity tri-complex between RMC-9805, cyclophilin A results suppression signaling downstream KRASG12D(ON) by disrupting its interactions effectors such as RAF...
Abstract Activating RAS mutations are among the most common drivers of human cancers. Upregulation RAS-MAPK signaling leads to sustained cell proliferation and immune escape via tumor cell-intrinsic modulation molecules crosstalk with microenvironment (TME). Major epithelial tumors harboring G12D variant, oncogenic KRAS mutation, remain an unmet medical need. The investigational agent RMC-9805, a RAS(ON) G12D-selective covalent inhibitor, exhibits potent antitumor activity in xenograft...
Abstract Activating mutations in KRAS drive tumorigenesis pancreatic ductal adenocarcinoma (PDAC), promoting tumor cell proliferation and contributing to an immunosuppressive microenvironment (TME) rendering PDAC tumors insensitive immunotherapy. RAS(ON) multi-selective inhibitors, such as daraxonrasib (RMC-6236) RMC-7977, target the active state of RAS, with potent anti-tumor activity murine models. Here, we report that inhibition led rapid profound regressions immunocompetent mice,...
Abstract Major epithelial tumors harboring the cancer driver KRASG12D, most common oncogenic KRAS mutation1, remain an outstanding unmet medical need. While RAS primarily promotes tumor progression through sustained cellular proliferation, there is also increasing evidence that it adversely shapes microenvironment (TME) induction of immuno-suppressive cytokines2, downregulation MHCI, and modulation checkpoint proteins3. KRASG12D oncoproteins can be selectively targeted with covalent...
Abstract RASG12D mutant cancers represent a significant unmet medical need with 55,000 new diagnoses annually in the US. The mutation increases abundance of active, GTP-bound state RAS (RASG12D(ON)) and occurs commonly multiple tumor histotypes, including about 20%, 29% 17% colorectal, pancreatic, non-small cell lung cancers, respectively. RMC-6236, an investigational RASMULTI(ON) inhibitor currently clinical testing, selectively targets both wild-type variants, RASG12D(ON) has shown...
Abstract Activating mutations in KRAS drive tumorigenesis more than 90% of cases pancreatic ductal adenocarcinoma (PDAC), promoting tumor cell proliferation and survival contributing to an immunosuppressive microenvironment (TME). RAS(ON) multi-selective inhibitors, such as RMC-6236 RMC-7977, potently block the active state mutant wild-type RAS isoforms show profound anti-tumor activity PDAC murine models1. Here, we utilized a panel immunocompetent mouse models evaluate extent which adaptive...
Abstract Oncogenic RAS promotes carcinogenesis by sustaining cell proliferation and orchestrating immune escape. We others have shown that inhibition combined with checkpoint blockade (ICB) prolongs durability of response in immunogenic, RAS-driven preclinical models. Clinical data most patients treated KRAS G12C(OFF) inhibitors develop resistance through reactivation the pathway. previously demonstrated combination a RAS(ON) G12C-selective inhibitor multi-selective can overcome mechanisms...
Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that driven by oncogenic RAS mutations in >90% of cases. Daraxonrasib (RMC-6236) orally bioavailable RAS(ON) multi-selective tri-complex inhibitor with broad-spectrum activity against mutant and wild-type variants N, H KRAS. We reported encouraging efficacy daraxonrasib at tolerated dose levels 160 to 300 mg daily as a data cutoff 23 Jul 2024 patients previously treated, metastatic PDAC, median progression free...
Summary Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by mutations. However, impact inhibiting functions in normal tissues is not known. RMC-7977 highly selective inhibitor active (GTP-bound) forms KRAS, HRAS, and NRAS, with affinity for both mutant wild type (WT) variants. As >90% pancreatic ductal adenocarcinoma (PDAC) cases activating mutations KRAS , we assessed therapeutic comprehensive range PDAC...
The neurotrophin-3 (NT-3) receptor tropomyosin kinase C (TrkC/NTRK3) has been described as a dependence and, such, triggers apoptosis in the absence of its ligand NT-3. This proapoptotic activity proposed to confer tumor suppressor this classic tyrosine (RTK). By investigating interacting partners that might facilitate TrkC-induced cell death, we have identified basic helix-loop-helix (bHLH) transcription factor Hey1 and importin-α3 (karyopherin alpha 4 [KPNA4]) direct interactors TrkC...
<p>Supplementary Figure 1 shows RMC-6236 crystal structure in tri-complex, as well biophysical and cellular potencies of by genotype. Supplementary 2 demonstrates dose-dependent anti-tumor activities at tolerable doses; pharmacodynamic effects on RAS signaling NCI-H441 xenograft tumors assessed IHC, relatively refractory KP-4 NCI-H2122 human DUSP6 mRNA expression vivo. 3 genotype dependent response across NSCLC, PDAC CRC; potential modifiers to the durability KRASG12C NSCLC models upon...
Abstract KRAS is the most frequently mutated oncogene in pancreatic ductal adenocarcinoma (PDAC), with KRASG12D driving initiation and progression of ~40% tumors. Mutant proteins exist predominantly GTP-bound (RAS(ON)) state, leading to excessive downstream signaling via interaction effectors such as RAF kinases. RMC-9805 an orally bioavailable, mutant-selective covalent inhibitor active state KRASG12D. RM-044, used here, corresponding representative preclinical tool compound. cyclophilin A...
Abstract Mutant KRAS is present in more than 80% pancreatic cancer, promotes cancer cell survival, and protects cells from immune recognition attack. We have shown that inhibitors of the active state RAS (RAS(ON)) promote neoantigen synergize with immunotherapy preclinical immunogenic models. 1 evaluated impact RMC-6236, an investigational RASMULTI(ON) inhibitor on anti-tumor activity tumor microenvironment (TME) remodeling two congenic KRASG12D/+ GEMM-derived PDAC models resistant to...