Combination of Type I and Type II MET Tyrosine Kinase Inhibitors as Therapeutic Approach to Prevent Resistance.

MET-targeted therapies are clinically effective in -amplified and exon 14 deletion mutant (ex14) non-small cell lung cancers (NSCLCs), but their efficacy is limited by the development of drug resistance. Structurally distinct MET tyrosine kinase inhibitors (TKIs) (type I/II) have been developed or are under clinical evaluation, which may overcome MET-mediated drug resistance mechanisms. In this study, we assess secondary MET mutations likely to emerge in response to treatment with single-agent or combinations of type I/type II MET TKIs using TPR-MET transformed Ba/F3 cell mutagenesis assays.

EGFR Inhibition Enhances the Cellular Uptake and Antitumor-Activity of the HER3 Antibody-Drug Conjugate HER3-DXd.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard-of-care treatment for -mutant non-small cell lung cancers (NSCLC). However, most patients develop acquired drug resistance to EGFR TKIs. HER3 is a unique pseudokinase member of the ERBB family that functions by dimerizing with other ERBB family members (EGFR and HER2) and is frequently overexpressed in -mutant NSCLC.

Dynamic single-cell RNA sequencing identifies immunotherapy persister cells following PD-1 blockade.

Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing.

Use of Patient-Derived Tumor Organotypic Spheroids to Identify Combination Therapies for Mutant Non-Small Cell Lung Cancer.

Purpose: Evaluating drug responses using primary patient-derived cells represents a potentially rapid and efficient approach to screening for new treatment approaches. Here, we sought to identify neratinib combinations in mutant non-small cell lung cancer (NSCLC) patient enograft-erived rganotypic pheroids (XDOTS) using a short-term system.

Experimental Design: We generated two mutant NSCLC PDX models [DFCI359 ( exon19 755_757LREdelinsRP) and DFCI315 ( exon20 V777_G778insGSP)] and used the PDX tumors to generate XDOTS.

A High-Throughput Immune-Oncology Screen Identifies EGFR Inhibitors as Potent Enhancers of Antigen-Specific Cytotoxic T-lymphocyte Tumor Cell Killing.

We developed a screening assay in which luciferized ID8 expressing OVA was cocultured with transgenic CD8 T cells specifically recognizing the model antigen in an H-2b-restricted manner. The assay was screened with a small-molecule library to identify compounds that inhibit or enhance T cell-mediated killing of tumor cells. Erlotinib, an EGFR inhibitor, was the top compound that enhanced T-cell killing of tumor cells.

Mycoplasma infection and hypoxia initiate succinate accumulation and release in the VM-M3 cancer cells.

Succinate is known to act as an inflammatory signal in classically activated macrophages through stabilization of HIF-1α leading to IL-1β production. Relevant to this, hypoxia is known to drive succinate accumulation and release into the extracellular milieu. The metabolic alterations associated with succinate release during inflammation and under hypoxia are poorly understood.

Quantification of metastatic load in a syngeneic murine model of metastasis.

Bioluminescence imaging (BLI) is an established method for evaluating metastatic load in preclinical cancer models; however, BLI can produce observational error due to differences in substrate concentration and signal depth. In our syngeneic murine model of metastasis (VM-M3), we used a quantitative polymerase chain reaction (qPCR) method of DNA quantification to bypass these limitations. Liver, spleen, and brain from VM/Dk (VM) mice bearing VM-M3 tumor cells were first imaged ex vivo with BLI.