A5046001195- Lung Cancer Treatments and Mutations
- Cancer-related Molecular Pathways
- RNA modifications and cancer
- Cancer Immunotherapy and Biomarkers
- NF-κB Signaling Pathways
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Ubiquitin and proteasome pathways
- Immune Response and Inflammation
- PI3K/AKT/mTOR signaling in cancer
- interferon and immune responses
- Protein Kinase Regulation and GTPase Signaling
- Reproductive System and Pregnancy
- Cancer Research and Treatments
- CAR-T cell therapy research
- IL-33, ST2, and ILC Pathways
- Radiopharmaceutical Chemistry and Applications
- Immunotherapy and Immune Responses
- Signaling Pathways in Disease
- Monoclonal and Polyclonal Antibodies Research
- Nanoparticle-Based Drug Delivery
- Heat shock proteins research
- Chemokine receptors and signaling
- Immune cells in cancer
- Pancreatic and Hepatic Oncology Research
Revolution Medicines (United States)
2020-2025
Coherus BioSciences (United States)
2018
University of California, Berkeley
2010-2016
University of California, San Francisco
2008-2013
Abstract RAS oncogenes (collectively NRAS , HRAS and especially KRAS ) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 61 1 . Small molecule inhibitors of KRAS(G12C) oncoprotein have demonstrated clinical efficacy patients multiple cancer types led to regulatory approvals for treatment non-small cell lung 2,3 Nevertheless, G12C account only around 15% -mutated cancers 4,5 there no approved majority tumours containing other...
Toll-like receptors (TLRs) on host cells are chronically engaged by microbial ligands during homeostatic conditions. These signals do not cause inflammatory immune responses in unperturbed mice, even though they drive innate and adaptive when combating infections. A20 is a ubiquitin-modifying enzyme that restricts exogenous TLR-induced signals. We show MyD88-dependent TLR the spontaneous T cell myeloid activation, cachexia, premature lethality seen A20-deficient mice. have used broad...
Some mature natural killer (NK) cells cannot be inhibited by major histocompatibility complex (MHC) I molecules, either because they lack corresponding inhibitory receptors or the host lacks MHC ligands for receptors. Such NK nevertheless remain self-tolerant and exhibit a generalized hyporesponsiveness to stimulation through activating To address whether cell responsiveness is set only during differentiation process, we transferred from wild-type (WT) I–deficient hosts vice versa....
Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition active RAS potentially desirable. Here, we evaluated the antitumor activity RAS(ON) multiselective tricomplex inhibitor RMC-7977 and dissected mechanisms response tolerance in KRASG12C-mutant non-small cell lung cancer (NSCLC). Broad-spectrum reversible RASGTP with or without concurrent covalent targeting yielded superior differentiated across diverse...
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 Psoriasis is a chronic, inflammatory skin disease caused by combination of environmental and genetic factors. The Tnip1 gene encodes A20 binding inhibitor NF-κB-1 (ABIN-1) protein strongly associated with susceptibility to psoriasis in humans. ABIN-1, widely expressed ubiquitin-binding protein, restricts TNF- TLR-induced signals. In this study, we report that mice lacking ABIN-1 specifically dendritic cells (DCs), ABIN-1fl CD11c-Cre mice, exhibit perturbed immune homeostasis....
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 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 The guanine nucleotide exchange factor (GEF) protein SOS1 activates RAS by promoting its conversion from the GDP-bound RAS(OFF) state to GTP-bound RAS(ON) state. catalyzes or accelerates this reaction in response upstream signals conveyed a range of growth receptors. It acts release tightly bound GDP and thereby facilitating binding GTP, which is present at higher intracellular concentrations than GDP, generate RAS(ON). itself activated through an allosteric site on protein, leads...
Abstract Many NK cells express inhibitory receptors that bind self-MHC class I (MHC I) molecules and prevent killing of self-cells, while enabling MHC I–deficient cells. But tolerance also occurs for lack I, all in animals. In both cases, are unresponsive to hyporesponsive when stimulated through activating receptors, suggesting hyporesponsiveness is responsible self-tolerance. We generated irradiation chimeras, or carried out adoptive transfers, with wild-type (WT) and/or hematopoietic WT...
Abstract KRASQ61H mutant cancers represent a significant unmet medical need and include common solid tumor histotypes such as non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), colorectal (CRC). Currently, there are no targeted inhibitors of in clinical development. Mutant RAS proteins exist predominantly the GTP-bound active RAS(ON) state, leading to excessive downstream signaling via interaction with effectors RAF kinases. The properties intrinsic GTPase cycle...
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...
<p>Supplementary Figure S1. Activity of RAS inhibitors in immune-competent pre-clinical models KRASG12C-mutated NSCLC.</p>
<p>Supplementary Figure S10. MAPK pathway modulation in immune and stromal cell subsets response to active RAS inhibition.</p>
<p>Supplementary Figure S2. Models and mechanisms of acquired resistance to RAS inhibitors</p>
<p>Supplementary Figure S3. Acute effects of active RAS inhibition in the KP2 and KL2 KrasG12C-mutant lung adenocarcinoma models</p>
<p>Supplementary Figure S6. Histological heterogeneity of lung tumors in the Kras<sup>G12C/+</sup>;Lkb1<sup>-/</sup>- GEM model.</p>