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1.
Cancer Res ; 82(22): 4126-4138, 2022 11 15.
Article in English | MEDLINE | ID: mdl-36069866

ABSTRACT

Patient-derived xenograft (PDX) models are an effective preclinical in vivo platform for testing the efficacy of novel drugs and drug combinations for cancer therapeutics. Here we describe a repository of 79 genomically and clinically annotated lung cancer PDXs available from The Jackson Laboratory that have been extensively characterized for histopathologic features, mutational profiles, gene expression, and copy-number aberrations. Most of the PDXs are models of non-small cell lung cancer (NSCLC), including 37 lung adenocarcinoma (LUAD) and 33 lung squamous cell carcinoma (LUSC) models. Other lung cancer models in the repository include four small cell carcinomas, two large cell neuroendocrine carcinomas, two adenosquamous carcinomas, and one pleomorphic carcinoma. Models with both de novo and acquired resistance to targeted therapies with tyrosine kinase inhibitors are available in the collection. The genomic profiles of the LUAD and LUSC PDX models are consistent with those observed in patient tumors from The Cancer Genome Atlas and previously characterized gene expression-based molecular subtypes. Clinically relevant mutations identified in the original patient tumors were confirmed in engrafted PDX tumors. Treatment studies performed in a subset of the models recapitulated the responses expected on the basis of the observed genomic profiles. These models therefore serve as a valuable preclinical platform for translational cancer research. SIGNIFICANCE: Patient-derived xenografts of lung cancer retain key features observed in the originating patient tumors and show expected responses to treatment with standard-of-care agents, providing experimentally tractable and reproducible models for preclinical investigations.


Subject(s)
Adenocarcinoma of Lung , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Animals , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Heterografts , Xenograft Model Antitumor Assays , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/genetics , Disease Models, Animal
2.
J Exp Med ; 210(5): 1021-33, 2013 May 06.
Article in English | MEDLINE | ID: mdl-23589568

ABSTRACT

Activation-induced cytidine deaminase (AID) is critical in normal B cells to initiate somatic hypermutation and immunoglobulin class switch recombination. Accumulating evidence suggests that AID is also prooncogenic, inducing cancer-promoting mutations or chromosome rearrangements. In this context, we find that AID is expressed in >40% of primary human chronic lymphocytic leukemia (CLL) cases, consistent with other reports. Using a combination of human B lymphoid leukemia cells and mouse models, we now show that AID expression can be harnessed for antileukemic effect, after inhibition of the RAD51 homologous recombination (HR) factor with 4,4'-diisothiocyanatostilbene-2-2'-disulfonic acid (DIDS). As a proof of principle, we show that DIDS treatment inhibits repair of AID-initiated DNA breaks, induces apoptosis, and promotes cytotoxicity preferentially in AID-expressing human CLL. This reveals a novel antineoplastic role of AID that can be triggered by inhibition of HR, suggesting a potential new paradigm to treat AID-expressing tumors. Given the growing list of tumor types with aberrant AID expression, this novel therapeutic approach has potential to impact a significant patient population.


Subject(s)
Cytidine Deaminase/metabolism , Homologous Recombination/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/enzymology , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid/pharmacology , Active Transport, Cell Nucleus/drug effects , Active Transport, Cell Nucleus/radiation effects , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/enzymology , B-Lymphocytes/pathology , B-Lymphocytes/radiation effects , Cell Death/drug effects , Cell Death/radiation effects , Cell Line, Transformed , Cell Line, Tumor , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cytidine Deaminase/genetics , DNA Breaks, Double-Stranded/drug effects , DNA Breaks, Double-Stranded/radiation effects , DNA Repair/drug effects , DNA Repair/radiation effects , Gene Expression Regulation, Leukemic/drug effects , Gene Expression Regulation, Leukemic/radiation effects , Histones/metabolism , Homologous Recombination/drug effects , Homologous Recombination/radiation effects , Humans , Mice , Rad51 Recombinase/metabolism , Radiation, Ionizing
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