RESUMEN
PURPOSE: Although first-line crizotinib treatment leads to clinical benefit in ROS1+ lung cancer, high prevalence of crizotinib-resistant ROS1-G2032R (ROS1G2032R) mutation and progression in the central nervous system (CNS) represents a therapeutic challenge. Here, we investigated the antitumor activity of repotrectinib, a novel next-generation ROS1/TRK/ALK-tyrosine kinase inhibitor (TKI) in ROS1+ patient-derived preclinical models. EXPERIMENTAL DESIGN: Antitumor activity of repotrectinib was evaluated in ROS1+ patient-derived preclinical models including treatment-naïve and ROS1G2032R models and was further demonstrated in patients enrolled in an on-going phase I/II clinical trial (NCT03093116). Intracranial antitumor activity of repotrectinib was evaluated in a brain-metastasis mouse model. RESULTS: Repotrectinib potently inhibited in vitro and in vivo tumor growth and ROS1 downstream signal in treatment-naïve YU1078 compared with clinically available crizotinib, ceritinib, and entrectinib. Despite comparable tumor regression between repotrectinib and lorlatinib in YU1078-derived xenograft model, repotrectinib markedly delayed the onset of tumor recurrence following drug withdrawal. Moreover, repotrectinib induced profound antitumor activity in the CNS with efficient blood-brain barrier penetrating properties. Notably, repotrectinib showed selective and potent in vitro and in vivo activity against ROS1G2032R. These findings were supported by systemic and intracranial activity of repotrectinib observed in patients enrolled in the on-going clinical trial. CONCLUSIONS: Repotrectinib is a novel next-generation ROS1-TKI with improved potency and selectivity against treatment-naïve and ROS1G2032R with efficient CNS penetration. Our findings suggest that repotrectinib can be effective both as first-line and after progression to prior ROS1-TKI.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Reordenamiento Génico , Neoplasias Pulmonares/genética , Compuestos Macrocíclicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Pirazoles/farmacología , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Compuestos Macrocíclicos/uso terapéutico , Ratones , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Clinical benefit of ALK tyrosine kinase inhibitors (ALK-TKIs) in ALK-rearranged lung cancer has been limited by the inevitable development of acquired resistance, and bypass-molecular resistance mechanisms remain poorly understood. We investigated a novel therapeutic target through screening FDA-approved drugs in ALK-TKI-resistant models. Cerivastatin, the rate-limiting enzyme inhibitor of the mevalonate pathway, showed anti-cancer activity against ALK-TKI resistance in vitro/in vivo, accompanied by cytoplasmic retention and subsequent inactivation of transcriptional co-regulator YAP. The marked induction of YAP-targeted oncogenes (EGFR, AXL, CYR61, and TGFßR2) in resistant cells was abolished by cerivastatin. YAP silencing suppressed tumor growth in resistant cells, patient-derived xenografts, and EML4-ALK transgenic mice, whereas YAP overexpression decreased the responsiveness of parental cells to ALK inhibitor. In matched patient samples before/after ALK inhibitor treatment, nuclear accumulation of YAP was mainly detected in post-treatment samples. High expression of YAP in pretreatment samples was correlated with poor response to ALK-TKIs. Our findings highlight a crucial role of YAP in ALK-TKI resistance and provide a rationale for targeting YAP as a potential treatment option for ALK-rearranged patients with acquired resistance to ALK inhibitors.
Asunto(s)
Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proteínas de Ciclo Celular/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Factores de Transcripción/metabolismo , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Neoplasias Pulmonares/genética , Ratones , Ratones Desnudos , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Preclinical models that can better predict therapeutic activity in clinical trials are needed in this era of personalized cancer treatment. Herein, we established genomically and clinically annotated patient-derived xenografts (PDXs) from non-small-cell lung cancer (NSCLC) patients and investigated whether these PDXs would faithfully recapitulate patient responses to targeted therapy. METHODS: Patient-derived tumors were implanted in immunodeficient mice and subsequently expanded via re-implantation. Established PDXs were examined by light microscopy, genomic profiling, and in vivo drug testing, and the successful engraft rate was analyzed with the mutation profile, histology, or acquisition method. Finally, the drug responses of PDXs were compared with the clinical responses of the respective patients. RESULTS: Using samples from 122 patients, we established 41 NSCLC PDXs [30 adenocarcinoma (AD), 11 squamous cell carcinoma (SQ)], among which the following driver mutation were observed: 13 EGFR-mutant, 4 ALK-rearrangement, 1 ROS1-rearrangement, 1 PIK3CA-mutant, 1 FGFR1-amplification, and 2 KRAS-mutant. We rigorously characterized the relationship of clinical features to engraftment rate and latency rates. The engraft rates were comparable across histologic type. The AD engraft rate tended to be higher for surgically resected tissues relative to biopsies, whereas similar engraft rates was observed for SQ, irrespective of the acquisition method. Notably, EGFR-mutants demonstrated significantly longer latency time than EGFR-WT (86 vs. 37days, P = 0.007). The clinical responses were recapitulated by PDXs harboring driver gene alteration (EGFR, ALK, ROS1, or FGFR1) which regressed to their target inhibitors, suggesting that established PDXs comprise a clinically relevant platform. CONCLUSION: The establishment of genetically and clinically annotated NSCLC PDXs can yield a robust preclinical tool for biomarker, therapeutic target, and drug discovery.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Evaluación Preclínica de Medicamentos/métodos , Neoplasias Pulmonares/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Receptores ErbB/genética , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Desnudos , Ratones SCID , Terapia Molecular Dirigida , Mutación/genética , Estadificación de Neoplasias , Medicina de PrecisiónRESUMEN
Anaplastic lymphoma kinase (ALK) inhibitors are highly effective in patients with ALK fusion-positive lung cancer, but acquired resistance invariably emerges. Identification of secondary mutations has received considerable attention, but most cases cannot be explained by genetic causes alone, raising the possibility of epigenetic mechanisms in acquired drug resistance. Here, we investigated the dynamic changes in the transcriptome and enhancer landscape during development of acquired resistance to ALK inhibitors. Histone H3 lysine 27 acetylation (H3K27ac) was profoundly altered during acquisition of resistance, and enhancer remodeling induced expression changes in both miRNAs and mRNAs. Decreased H3K27ac levels and reduced miR-34a expression associated with the activation of target genes such as AXL. Panobinostat, a pan-histone deacetylase inhibitor, altered the H3K27ac profile and activated tumor-suppressor miRNAs such as miR-449, another member of the miR-34 family, and synergistically induced antiproliferative effects with ALK inhibitors on resistant cells, xenografts, and EML4-ALK transgenic mice. Paired analysis of patient samples before and after treatment with ALK inhibitors revealed that repression of miR-34a or miR-449a and activation of AXL were mutually exclusive of secondary mutations in ALK. Our findings indicate that enhancer remodeling and altered expression of miRNAs play key roles in cancer drug resistance and suggest that strategies targeting epigenetic pathways represent a potentially effective method for overcoming acquired resistance to cancer therapy.Significance: Epigenetic deregulation drives acquired resistance to ALK inhibitors in ALK-positive lung cancer. Cancer Res; 78(12); 3350-62. ©2018 AACR.