A5026875957- Synthesis and Biological Evaluation
- Synthesis and biological activity
- Cancer Immunotherapy and Biomarkers
- Monoclonal and Polyclonal Antibodies Research
- Immunotherapy and Immune Responses
- Lung Cancer Treatments and Mutations
- Click Chemistry and Applications
- Immune cells in cancer
- Bioactive Compounds and Antitumor Agents
- CAR-T cell therapy research
- Peptidase Inhibition and Analysis
- Cell Image Analysis Techniques
- Single-cell and spatial transcriptomics
- Protein Tyrosine Phosphatases
- Chemical Synthesis and Analysis
- T-cell and B-cell Immunology
- Adenosine and Purinergic Signaling
- Inflammatory mediators and NSAID effects
- Cell Adhesion Molecules Research
- Gastrointestinal motility and disorders
- PI3K/AKT/mTOR signaling in cancer
- Pharmaceutical studies and practices
- Galectins and Cancer Biology
- Cystic Fibrosis Research Advances
- Cancer-related Molecular Pathways
The Francis Crick Institute
2019-2024
University of California, Los Angeles
2024
Imperial College London
2019
University of Illinois Urbana-Champaign
2016
University of Illinois Chicago
2016
Combined targeting of KRAS-G12C, mTOR, and IGF1R enhances extends the response to recently developed KRAS-G12C inhibitors in lung cancer models.
Recently developed KRAS G12C inhibitory drugs are beneficial to lung cancer patients harboring mutations, but drug resistance frequently develops. Because of the immunosuppressive nature signaling network controlled by oncogenic KRAS, these can indirectly affect antitumor immunity, providing a rationale for their combination with immune checkpoint blockade. In this study, we have characterized how inhibition reverses immunosuppression driven in number preclinical models varying levels...
Abstract Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins tumor regression but ultimately fail to elicit cures. As result, there is an intense interest how best combine targeted therapies with other treatments, immunotherapies. However, preclinical systems for studying the interaction tumors host immune system are inadequate, part due low mutational burden genetically engineered mouse models. Here we set out develop models...
Abstract A major limitation to developing chimeric antigen receptor (CAR)-T cell therapies for solid tumors is identifying surface proteins highly expressed in but not normal tissues. Here, we identify Tyrosinase Related Protein 1 (TYRP1) as a CAR-T therapy target treat patients with cutaneous and rare melanoma subtypes unresponsive immune checkpoint blockade. TYRP1 primarily located intracellularly the melanosomes, small fraction being trafficked via vesicular transport. We develop...
Abstract Mouse models are critical in pre-clinical studies of cancer therapy, allowing dissection mechanisms through chemical and genetic manipulations that not feasible the clinical setting. In tumour microenvironment (TME), multiplexed imaging methods can provide a rich source information. However, application such technologies mouse tissues is still its infancy. Here we present workflow for studying TME using mass cytometry with panel 27 antibodies on frozen tissues. We optimise validate...
Abstract Oncogenic KRAS impairs antitumor immune responses. As effective strategies to combine inhibitors and immunotherapies have so far proven elusive, a better understanding of the mechanisms by which oncogenic drives evasion is needed identify approaches that could sensitize KRAS-mutant lung cancer immunotherapy. In vivo CRISPR–Cas9 screening in an immunogenic murine model identified promotes evasion, most notably via upregulation immunosuppressive COX2 cells. potently induced both mouse...
Abstract Mutant selective drugs targeting the inactive, GDP-bound form of KRAS G12C have been approved for use in lung cancer, but resistance develops rapidly. Here we an inhibitor, (RMC-4998) that targets RAS its active, GTP-bound form, to treat mutant cancer various immune competent mouse models. pathway reactivation after RMC-4998 treatment could be delayed using combined with a SHP2 which not only impacts tumour cell signalling also remodels microenvironment less immunosuppressive. In...
Kirsten rat sarcoma virus (KRAS)-G12C inhibition causes remodeling of the lung tumor immune microenvironment and synergistic responses to anti-PD-1 treatment, but only in T cell infiltrated tumors. To investigate mechanisms that restrain combination immunotherapy sensitivity immune-excluded tumors, we used imaging mass cytometry explore cellular distribution an immune-evasive KRAS mutant cancer model. Cellular spatial pattern characterization revealed a community where CD4
ABSTRACT Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins tumour regression but ultimately fail to cure cancers, leading intense interest how best combine them with other treatments, immunotherapies. However, preclinical systems for studying the interaction tumours host immune system are inadequate, part due low mutational burden genetically engineered mouse models. Here we set out develop models mutant KRAS-driven cancer an...
Abstract Mouse models are critical in pre-clinical studies of cancer therapy, allowing dissection mechanisms through chemical and genetic manipulations that not feasible the clinical setting. In tumour microenvironment (TME), multiplexed imaging methods can provide a rich source information. However, application such technologies mouse tissues is still its infancy. Here we present workflow for studying TME using mass cytometry with panel 27 antibodies on frozen tissues. We optimise validate...
Abstract Oncogenic mutations in KRAS are frequent non-small cell lung cancer and have been associated with poor prognosis. The recent development approval of KRASG12C mutant-specific inhibitors could change the clinical practice patients harboring mutations. However, early data indicate acquired resistance after initial responses. All being tested trials to date target GDP-bound (OFF state), which makes them vulnerable upstream pathway reactivation, as this will increase a GTP-bound (ON)...
Abstract Mouse models are critical in pre-clinical studies of cancer therapy, allowing dissection mechanisms through chemical and genetic manipulations that not feasible the clinical setting. In tumour microenvironment (TME), novel highly multiplexed imaging methods can provide a rich source information. However, application such technologies mouse tissues is still its infancy. Here we present workflow for studying TME using mass cytometry with panel 27 antibodies on frozen tissues. We...
ABSTRACT Oncogenic KRAS impairs anti-tumour immune responses, but effective strategies to combine inhibitors and immunotherapies have so far proven elusive. In vivo CRISPR-Cas9 screening in an immunogenic murine lung cancer model identifies mechanisms by which oncogenic promotes evasion, most notably expression of immunosuppressive cyclooxygenase-2 (COX-2) cells. was a potent inducer COX-2 both mouse human suppressed using inhibitors. acting via prostaglandin E2 (PGE2) resistance checkpoint...
ABSTRACT Mutant selective drugs targeting the inactive, GDP-bound form of KRAS G12C have been approved for use in lung cancer, but responses are short-lived due to rapid development resistance. In this study we a novel covalent tri-complex inhibitor, RMC-4998, that targets RAS its active, GTP-bound investigate treatment mutant cancer various immune competent mouse models. While (ON) inhibitor was more potent than (OFF) adagrasib, pathway reactivation still observed. This could be delayed...
ABSTRACT We recently showed that lung tumor specific KRAS-G12C inhibition causes remodelling of the immune microenvironment from cold to hot. As a result, is able synergise with anti-PD-1 treatment, but only in models were already moderately responsive checkpoint blockade at baseline. To investigate mechanisms restrain immunotherapy sensitivity non-responsive tumors, we used multiplex imaging mass cytometry explore spatial patterns highly evasive KRAS mutant murine Lewis Lung Cancer model....
<div>Abstract<p>Oncogenic KRAS impairs antitumor immune responses. As effective strategies to combine inhibitors and immunotherapies have so far proven elusive, a better understanding of the mechanisms by which oncogenic drives evasion is needed identify approaches that could sensitize KRAS-mutant lung cancer immunotherapy. <i>In vivo</i> CRISPR–Cas9 screening in an immunogenic murine model identified promotes evasion, most notably via upregulation immunosuppressive...
<p><i>In vivo</i> CRISPR–Cas9 screen identifies regulators of antitumor immunity. <b>A,</b> Schematic pooled screen. <b>B,</b> sgRNAs targeting genes depleted <i>in vitro</i> compared with nontarget controls. The CRISPR score is defined as the average log<sub>2</sub>-fold change in abundance sgRNA reads at day 28 (<i>in vitro</i>) vs. 0 for each gene. <b>C,</b> <i>Cflar</i> and...
<p>Tumor-intrinsic COX2 suppresses antitumor immunity. <b>A,</b> Kaplan–Meier survival of mice treated with 200 μg anti-NK1.1 and/or anti-CD8 or corresponding isotype control (<i>n</i> = 5–7 per group) after orthotopic transplantation <i>Ptgs2</i><sup>−<i>/</i>−</sup> cells. Treatment was initiated 3 days before and administered once weekly until endpoint. Analysis curves carried out using the log-rank (Mantel–Cox) test....
<p>In vivo screen identifies mediators of immune resistance and sensitivity</p>
<p>In vivo screen identifies mediators of immune resistance and sensitivity</p>
<p>Supplementary Figure 5. Flow cytometry gating strategies</p>
<p>Supplementary Figure 3. Oncogenic KRAS inhibits tumor-intrinsic IFN responses via Myc</p>
<p>Oncogenic KRAS drives immunosuppressive COX2 expression in lung adenocarcinoma. <b>A,</b> Immunoblot for (left) and ELISA analysis PGE2 concentration (right) KPAR cells treated with 10 nmol/L trametinib (MEKi) 24 hours or 48 hours. <b>B</b> <b>C,</b> (<b>B</b>) (<b>C</b>) KRAS<sup>G12C</sup> mouse cancer cell lines 100 MRTX849 <b>D,</b> mRNA 3LL ΔNRAS KPAR<sup>G12C</sup> orthotopic tumors...