RESUMO
Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most EGFR-mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. HER3-DXd is an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. This phase I, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg intravenously once every 3 weeks, the confirmed objective response rate by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1) was 39% [95% confidence interval (CI), 26.0-52.4], and median progression-free survival was 8.2 (95% CI, 4.4-8.3) months. Responses were observed in patients with known and unknown EGFR TKI resistance mechanisms. Clinical activity was observed across a broad range of HER3 membrane expression. The most common grade ≥3 treatment-emergent adverse events were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI-resistant cancers independent of resistance mechanisms, providing an approach to treat a broad range of drug-resistant cancers. SIGNIFICANCE: In metastatic EGFR-mutated NSCLC, after disease progression on EGFR TKI therapy, treatment approaches include genotype-directed therapy targeting a known resistance mechanism or chemotherapy. HER3-DXd demonstrated clinical activity spanning known and unknown EGFR TKI resistance mechanisms. HER3-DXd could present a future treatment option agnostic to the EGFR TKI resistance mechanism.See related commentary by Lim et al., p. 16.This article is highlighted in the In This Issue feature, p. 1.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Camptotecina/análogos & derivados , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Infusões Intravenosas , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Resultado do TratamentoRESUMO
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard-of-care treatment for EGFR-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 EGFR-mutant NSCLC. Although EGFR TKI resistance mechanisms do not lead to alterations in HER3, we hypothesized that targeting HER3 might improve efficacy of EGFR TKI. HER3-DXd is an antibody-drug conjugate (ADC) comprised of HER3-targeting antibody linked to a topoisomerase I inhibitor currently in clinical development. In this study, we evaluated the efficacy of HER3-DXd across a series of EGFR inhibitor-resistant, patient-derived xenografts and observed it to be broadly effective in HER3-expressing cancers. We further developed a preclinical strategy to enhance the efficacy of HER3-DXd through osimertinib pretreatment, which increased membrane expression of HER3 and led to enhanced internalization and efficacy of HER3-DXd. The combination of osimertinib and HER3-DXd may be an effective treatment approach and should be evaluated in future clinical trials in EGFR-mutant NSCLC patients. SIGNIFICANCE: EGFR inhibition leads to increased HER3 membrane expression and promotes HER3-DXd ADC internalization and efficacy, supporting the clinical development of the EGFR inhibitor/HER3-DXd combination in EGFR-mutant lung cancer.See related commentary by Lim et al., p. 18.
Assuntos
Antineoplásicos/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Imunoconjugados/metabolismo , Receptor ErbB-3/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Humanos , CamundongosRESUMO
To systematically define molecular features in human tumor cells that determine their degree of sensitivity to human allogeneic natural killer (NK) cells, we quantified the NK cell responsiveness of hundreds of molecularly annotated 'DNA-barcoded' solid tumor cell lines in multiplexed format and applied genome-scale CRISPR-based gene-editing screens in several solid tumor cell lines, to functionally interrogate which genes in tumor cells regulate the response to NK cells. In these orthogonal studies, NK cell-sensitive tumor cells tend to exhibit 'mesenchymal-like' transcriptional programs; high transcriptional signature for chromatin remodeling complexes; high levels of B7-H6 (NCR3LG1); and low levels of HLA-E/antigen presentation genes. Importantly, transcriptional signatures of NK cell-sensitive tumor cells correlate with immune checkpoint inhibitor (ICI) resistance in clinical samples. This study provides a comprehensive map of mechanisms regulating tumor cell responses to NK cells, with implications for future biomarker-driven applications of NK cell immunotherapies.
Assuntos
Citotoxicidade Imunológica/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Inibidores de Checkpoint Imunológico/farmacologia , Células Matadoras Naturais/fisiologia , Células Alógenas/fisiologia , Animais , Antígenos B7/genética , Linhagem Celular Tumoral , Montagem e Desmontagem da Cromatina/fisiologia , Testes Imunológicos de Citotoxicidade/métodos , Citotoxicidade Imunológica/fisiologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Genoma Humano , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Camundongos Endogâmicos NOD , Ensaios Antitumorais Modelo de Xenoenxerto , Antígenos HLA-ERESUMO
PURPOSE: Androgen receptor (AR) inhibition can upregulate c-MET expression, which may be a resistance mechanism driving progression of castration-resistant prostate cancer (CRPC). We conducted a phase I trial investigating the safety and pharmacokinetics of a potent c-MET inhibitor, crizotinib, with the AR antagonist, enzalutamide, in CRPC. PATIENTS AND METHODS: Employing a 3+3 dose-escalation design, we tested three dose levels of crizotinib (250 mg daily, 200 mg twice a day, and 250 mg twice a day) with standard-dose enzalutamide (160 mg daily). The primary endpoint was rate of dose-limiting toxicities (DLTs). Tolerability and pharmacokinetics profile were secondary endpoints. RESULTS: Twenty-four patients were enrolled in the dose-escalation (n = 16) and dose-expansion (n = 8) phases. Two DLTs occurred in dose escalation (grade 3 alanine aminotransferase elevation). The MTD of crizotinib was 250 mg twice a day. Most frequent treatment-related adverse events were fatigue (50%), transaminitis (38%), nausea (33%), and vomiting, constipation, and diarrhea (21% each). Grade ≥3 events (25%) included transaminitis (n = 2), fatigue (n = 1), hypertension (n = 1), pulmonary embolism (n = 1), and a cardiac event encompassing QTc prolongation/ventricular arrhythmia/cardiac arrest. Median progression-free survival was 5.5 months (95% confidence interval, 2.8-21.2). Pharmacokinetics analysis at the MTD (n = 12) revealed a mean C max ss of 104 ± 45 ng/mL and AUCτ ss of 1,000 ± 476 ngâ¢h/mL, representing a 74% decrease in crizotinib systemic exposure relative to historical data (C max ss, 315 ng/mL and AUCτ ss, 3,817 ngâ¢h/mL). CONCLUSIONS: Concurrent administration of enzalutamide and crizotinib resulted in a clinically significant 74% decrease in systemic crizotinib exposure. Further investigation of this combination in CRPC is not planned. Our results highlight the importance of evaluating pharmacokinetics interactions when evaluating novel combination strategies in CRPC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Receptores Androgênicos/química , Idoso , Idoso de 80 Anos ou mais , Benzamidas/administração & dosagem , Crizotinibe/administração & dosagem , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Feniltioidantoína/administração & dosagem , Prognóstico , Neoplasias de Próstata Resistentes à Castração/patologia , Taxa de SobrevidaRESUMO
The additional information of this manuscript originally stated that the authors declare no competing interests. This statement was incorrect, and should instead have stated the following:M.C.H. has the following competing interests to declare: Equity interest at Molecular MD; Consulting at Molecular MD, Blueprint Medicines, Deciphera Pharmaceuticals; Expert Testimony at Novartis; Licensed patent with royalty payments at Novartis. The remaining authors have no competing interests to declare.The authors apologise for any convenience this may have caused.
RESUMO
BACKGROUND: Most patients with KIT-mutant gastrointestinal stromal tumours (GISTs) benefit from imatinib, but treatment resistance results from outgrowth of heterogeneous subclones with KIT secondary mutations. Once resistance emerges, targeting KIT with tyrosine kinase inhibitors (TKIs) sunitinib and regorafenib provides clinical benefit, albeit of limited duration. METHODS: We systematically explored GIST resistance mechanisms to KIT-inhibitor TKIs that are either approved or under investigation in clinical trials: the studies draw upon GIST models and clinical trial correlative science. We subsequently modelled in vitro a rapid TKI alternation approach against subclonal heterogeneity. RESULTS: Each of the KIT-inhibitor TKIs targets effectively only a subset of KIT secondary mutations in GIST. Regorafenib and sunitinib have complementary activity in that regorafenib primarily inhibits imatinib-resistance mutations in the activation loop, whereas sunitinib inhibits imatinib-resistance mutations in the ATP-binding pocket. We find that rapid alternation of sunitinib and regorafenib suppresses growth of polyclonal imatinib-resistant GIST more effectively than either agent as monotherapy. CONCLUSIONS: Our data highlight that heterogeneity of KIT secondary mutations is the main mechanism of tumour progression to KIT inhibitors in imatinib-resistant GIST patients. Therapeutic combinations of TKIs with complementary activity against resistant mutations may be useful to suppress growth of polyclonal imatinib-resistance in GIST.
Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Animais , Células CHO , Ensaios Clínicos Fase II como Assunto , Cricetulus , Resistencia a Medicamentos Antineoplásicos , Feminino , Neoplasias Gastrointestinais/enzimologia , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/enzimologia , Tumores do Estroma Gastrointestinal/genética , Humanos , Mesilato de Imatinib/farmacologia , Camundongos , Camundongos Nus , Compostos de Fenilureia/farmacologia , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Piridinas/farmacologia , Sunitinibe/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hundreds of genetically characterized cell lines are available for the discovery of genotype-specific cancer vulnerabilities. However, screening large numbers of compounds against large numbers of cell lines is currently impractical, and such experiments are often difficult to control. Here we report a method called PRISM that allows pooled screening of mixtures of cancer cell lines by labeling each cell line with 24-nucleotide barcodes. PRISM revealed the expected patterns of cell killing seen in conventional (unpooled) assays. In a screen of 102 cell lines across 8,400 compounds, PRISM led to the identification of BRD-7880 as a potent and highly specific inhibitor of aurora kinases B and C. Cell line pools also efficiently formed tumors as xenografts, and PRISM recapitulated the expected pattern of erlotinib sensitivity in vivo.
Assuntos
Código de Barras de DNA Taxonômico/métodos , Resistencia a Medicamentos Antineoplásicos/genética , Técnicas de Genotipagem/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/classificação , Neoplasias/genética , Animais , Linhagem Celular Tumoral , Humanos , CamundongosRESUMO
Acquired mutations in the hematopoietic transcription factor GATA binding protein-1 (GATA1) are found in megakaryoblasts from nearly all individuals with Down syndrome with transient myeloproliferative disorder (TMD, also called transient leukemia) and the related acute megakaryoblastic leukemia (DS-AMKL, also called DS-AML M7). These mutations lead to production of a variant GATA1 protein (GATA1s) that is truncated at its N terminus. To understand the biological properties of GATA1s and its relation to DS-AMKL and TMD, we used gene targeting to generate Gata1 alleles that express GATA1s in mice. We show that the dominant action of GATA1s leads to hyperproliferation of a unique, previously unrecognized yolk sac and fetal liver progenitor, which we propose accounts for the transient nature of TMD and the restriction of DS-AMKL to infants. Our observations raise the possibility that the target cells in other leukemias of infancy and early childhood are distinct from those in adult leukemias and underscore the interplay between specific oncoproteins and potential target cells.
Assuntos
Proteínas de Ligação a DNA/genética , Mutação , Fatores de Transcrição/genética , Adulto , Fatores Etários , Animais , Diferenciação Celular , Células Cultivadas , Síndrome de Down/genética , Embrião de Mamíferos , Fatores de Ligação de DNA Eritroide Específicos , Fator de Transcrição GATA1 , Marcação de Genes , Hematopoese/genética , Humanos , Lactente , Leucemia Megacarioblástica Aguda/genética , Fígado/citologia , Fígado/embriologia , Megacariócitos , Camundongos , TransfecçãoRESUMO
Transcription factor GATA-1 reprograms immature myeloid cells to three different hematopoietic lineages-erythroid cells, megakaryocytes, and eosinophils. GATA-1 is essential for maturation of erythroid and megakaryocytic precursors, as revealed by gene targeting in mice. Here we demonstrate that deletion of a high-affinity GATA-binding site in the GATA-1 promoter, an element presumed to mediate positive autoregulation of GATA-1 expression, leads to selective loss of the eosinophil lineage. These findings suggest that GATA-1 is required for specification of this lineage during hematopoietic development. Mice lacking the ability to produce eosinophils should prove useful in ascertaining the role of eosinophils in a variety of inflammatory or allergic disorders.