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1.
Mol Cancer Ther ; 19(10): 2044-2056, 2020 10.
Article in English | MEDLINE | ID: mdl-32747419

ABSTRACT

Small molecule inhibitors targeting mutant EGFR are standard of care in non-small cell lung cancer (NSCLC), but acquired resistance invariably develops through mutations in EGFR or through activation of compensatory pathways such as cMet. Amivantamab (JNJ-61186372) is an anti-EGFR and anti-cMet bispecific low fucose antibody with enhanced Fc function designed to treat tumors driven by activated EGFR and/or cMet signaling. Potent in vivo antitumor efficacy is observed upon amivantamab treatment of human tumor xenograft models driven by mutant activated EGFR, and this activity is associated with receptor downregulation. Despite these robust antitumor responses in vivo, limited antiproliferative effects and EGFR/cMet receptor downregulation by amivantamab were observed in vitro Interestingly, in vitro addition of isolated human immune cells notably enhanced amivantamab-mediated EGFR and cMet downregulation, leading to antibody dose-dependent cancer cell killing. Through a comprehensive assessment of the Fc-mediated effector functions, we demonstrate that monocytes and/or macrophages, through trogocytosis, are necessary and sufficient for Fc interaction-mediated EGFR/cMet downmodulation and are required for in vivo antitumor efficacy. Collectively, our findings represent a novel Fc-dependent macrophage-mediated antitumor mechanism of amivantamab and highlight trogocytosis as an important mechanism of action to exploit in designing new antibody-based cancer therapies.


Subject(s)
Antibodies, Bispecific/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Macrophages/metabolism , Monocytes/metabolism , Antibodies, Bispecific/pharmacology , Antineoplastic Agents, Immunological/pharmacology , Humans
2.
Mol Cancer Ther ; 14(10): 2167-74, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26253517

ABSTRACT

The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription elongation. In hematologic cancers, BET proteins have been shown to regulate expression of MYC and other genes that are important to disease pathology. Pharmacologic inhibition of BET protein binding has been shown to inhibit tumor growth in MYC-dependent cancers, such as multiple myeloma. In this study, we demonstrate that small cell lung cancer (SCLC) cells are exquisitely sensitive to growth inhibition by the BET inhibitor JQ1. JQ1 treatment has no impact on MYC protein expression, but results in downregulation of the lineage-specific transcription factor ASCL1. SCLC cells that are sensitive to JQ1 are also sensitive to ASCL1 depletion by RNAi. Chromatin immunoprecipitation studies confirmed the binding of the BET protein BRD4 to the ASCL1 enhancer, and the ability of JQ1 to disrupt the interaction. The importance of ASCL1 as a potential driver oncogene in SCLC is further underscored by the observation that ASCL1 is overexpressed in >50% of SCLC specimens, an extent greater than that observed for other putative oncogenes (MYC, MYCN, and SOX2) previously implicated in SCLC. Our studies have provided a mechanistic basis for the sensitivity of SCLC to BET inhibition and a rationale for the clinical development of BET inhibitors in this disease with high unmet medical need.


Subject(s)
Antineoplastic Agents/pharmacology , Azepines/pharmacology , Basic Helix-Loop-Helix Transcription Factors/genetics , Lung Neoplasms/metabolism , Nuclear Proteins/metabolism , Small Cell Lung Carcinoma/metabolism , Transcription Factors/metabolism , Triazoles/pharmacology , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cell Cycle Proteins , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Resistance, Neoplasm/genetics , Drug Screening Assays, Antitumor , Enhancer Elements, Genetic , Gene Expression , Gene Expression Regulation, Neoplastic/drug effects , Humans , Inhibitory Concentration 50 , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Protein Binding , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/genetics , Transcriptome/drug effects
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