RESUMEN
BACKGROUND: RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown. METHODS: We enrolled patients with RET-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS: In the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events. CONCLUSIONS: In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).
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Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores , Pirazoles/administración & dosificación , Piridinas/administración & dosificación , Neoplasias de la Tiroides/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Hipertensión/inducido químicamente , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas c-ret/análisis , Proteínas Proto-Oncogénicas c-ret/genética , Pirazoles/efectos adversos , Piridinas/efectos adversos , Transaminasas/sangre , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: RET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown. METHODS: We enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS: In the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event. CONCLUSIONS: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores , Pirazoles/administración & dosificación , Piridinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Hipertensión/inducido químicamente , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Mutación , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas c-ret/análisis , Proteínas Proto-Oncogénicas c-ret/genética , Pirazoles/efectos adversos , Piridinas/efectos adversos , Transaminasas/sangre , Resultado del Tratamiento , Adulto JovenRESUMEN
RAF inhibitors have transformed treatment for patients with BRAFV600-mutant cancers, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAFV600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by a narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAFV600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 ± binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in patients with BRAF-mutant cancer who were refractory to approved RAF inhibitors. Significance: PF-07799933 treatment was associated with antitumor activity against BRAFV600- and non-V600-mutant cancers preclinically and in treatment-refractory patients, and PF-07799933 could be safely combined with a MEK inhibitor. The novel, rapid pharmacokinetics (PK)-informed dose escalation design provides a new paradigm for accelerating the testing of next-generation targeted therapies early in clinical development.
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Resistencia a Antineoplásicos , Mutación , Neoplasias , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas B-raf , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Animales , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Ratones , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Masculino , Persona de Mediana Edad , Bencimidazoles/farmacocinética , Bencimidazoles/uso terapéutico , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacología , Anciano , Adulto , Línea Celular TumoralRESUMEN
Rare circulating tumor cells (CTCs) present in the bloodstream of patients with cancer provide a potentially accessible source for detection, characterization, and monitoring of nonhematological cancers. We previously demonstrated the effectiveness of a microfluidic device, the CTC-Chip, in capturing these epithelial cell adhesion molecule (EpCAM)-expressing cells using antibody-coated microposts. Here, we describe a high-throughput microfluidic mixing device, the herringbone-chip, or "HB-Chip," which provides an enhanced platform for CTC isolation. The HB-Chip design applies passive mixing of blood cells through the generation of microvortices to significantly increase the number of interactions between target CTCs and the antibody-coated chip surface. Efficient cell capture was validated using defined numbers of cancer cells spiked into control blood, and clinical utility was demonstrated in specimens from patients with prostate cancer. CTCs were detected in 14 of 15 (93%) patients with metastatic disease (median = 63 CTCs/mL, mean = 386 ± 238 CTCs/mL), and the tumor-specific TMPRSS2-ERG translocation was readily identified following RNA isolation and RT-PCR analysis. The use of transparent materials allowed for imaging of the captured CTCs using standard clinical histopathological stains, in addition to immunofluorescence-conjugated antibodies. In a subset of patient samples, the low shear design of the HB-Chip revealed microclusters of CTCs, previously unappreciated tumor cell aggregates that may contribute to the hematogenous dissemination of cancer.
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Separación Celular/instrumentación , Técnicas Analíticas Microfluídicas/instrumentación , Células Neoplásicas Circulantes/patología , Secuencia de Bases , Ingeniería Biomédica , Agregación Celular , Línea Celular Tumoral , ADN de Neoplasias/genética , ADN de Neoplasias/aislamiento & purificación , Humanos , Neoplasias Pulmonares/sangre , Masculino , Proteínas de Fusión Oncogénica/genética , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/secundarioRESUMEN
Rationally targeted therapies have transformed cancer treatment, but many patients develop resistance through bypass signaling pathway activation. PF-07284892 (ARRY-558) is an allosteric SHP2 inhibitor designed to overcome bypass-signaling-mediated resistance when combined with inhibitors of various oncogenic drivers. Activity in this setting was confirmed in diverse tumor models. Patients with ALK fusion-positive lung cancer, BRAFV600E-mutant colorectal cancer, KRASG12D-mutant ovarian cancer, and ROS1 fusion-positive pancreatic cancer who previously developed targeted therapy resistance were treated with PF-07284892 on the first dose level of a first-in-human clinical trial. After progression on PF-07284892 monotherapy, a novel study design allowed the addition of oncogene-directed targeted therapy that had previously failed. Combination therapy led to rapid tumor and circulating tumor DNA (ctDNA) responses and extended the duration of overall clinical benefit. SIGNIFICANCE: PF-07284892-targeted therapy combinations overcame bypass-signaling-mediated resistance in a clinical setting in which neither component was active on its own. This provides proof of concept of the utility of SHP2 inhibitors in overcoming resistance to diverse targeted therapies and provides a paradigm for accelerated testing of novel drug combinations early in clinical development. See related commentary by Hernando-Calvo and Garralda, p. 1762. This article is highlighted in the In This Issue feature, p. 1749.
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Neoplasias Pulmonares , Proteínas Tirosina Quinasas , Humanos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Oncogenes , Atención Dirigida al PacienteRESUMEN
PURPOSE: ARRY-382 (PF-07265804) is a selective inhibitor of colony-stimulating factor-1 receptor. We evaluated the safety and preliminary efficacy of ARRY-382 plus pembrolizumab in patients with advanced solid tumors. PATIENTS AND METHODS: This was an open-label, multicenter, Phase 1b/2 study (NCT02880371) performed over September 1, 2016 to October 24, 2019. In the Phase 1b dose-escalation, patients with selected advanced solid tumors received ARRY-382 [starting dose 200 mg once daily (QD) orally] plus pembrolizumab [2 mg/kg intravenously (IV) every 3 weeks (Q3W)]. Phase 2 patients had: Pancreatic ductal adenocarcinoma (PDA); programmed cell death protein-1 (PD-1)/PD-ligand 1 (PD-L1) inhibitor-refractory (PD-1/PD-L1 IR) advanced solid tumors; or platinum-resistant ovarian cancer (prOVCA). Patients received ARRY-382 at the maximum tolerated dose (MTD) of 300 mg QD plus pembrolizumab 200 mg IV Q3W. RESULTS: Primary endpoints of dose-limiting toxicities (DLT; Phase 1b) and objective response rate (Phase 2) were met. In Phase 1b, 19 patients received ARRY-382 200-400 mg. Three patients reported DLTs. The MTD of ARRY-382 (plus pembrolizumab) was 300 mg QD. In Phase 1b, 2 patients (10.5%) had confirmed partial response (PR): 1 with PDA and 1 with ovarian cancer, lasting 29.2 and 3.1 months, respectively. In Phase 2, there were 27, 19, and 11 patients in the PDA, PD-1/PD-L1 IR, and prOVCA cohorts, respectively. One patient (3.7%) with PDA had a PR lasting 2.4 months. The most frequent ARRY-382-related adverse events were increased transaminases (10.5%-83.3%) and increased creatine phosphokinase (18.2%-50.0%). CONCLUSIONS: Although limited clinical benefit was observed, ARRY-382 plus pembrolizumab was well tolerated.
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Neoplasias Ováricas , Receptor de Muerte Celular Programada 1 , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1 , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Proteínas QuinasasRESUMEN
RNAi is widely applied to inhibit expression of specific genes, but it is limited by variable efficiency and specificity of empirically designed siRNA or shRNA constructs. This complicates studies targeting individual genes and significantly impairs large-scale screens using genome-wide knockdown libraries. Here, we show that ectopic expression of the RISC slicer Argonaute-2 (Ago2, eIF2C2) dramatically enhances RNAi specifically for mRNA targets with perfectly matched binding sites. This effect depends on its endonuclease activity and is uncoupled from its regulation of microRNA expression. To model the application of Ago2 coexpression with shRNA knockdown, we targeted the EGF receptor (EGFR) in lung cancer cells exhibiting oncogene addiction to EGFR. Whereas multiple empirically designed shRNA constructs exhibited highly divergent efficiencies in mediating EGFR knockdown and cell killing, coexpression of Ago2 resulted in uniform and highly specific target gene suppression and apoptosis in EGFR-dependent cells. Codelivery of Ago2 with shRNA constructs or siRNA duplexes thus provides a strategy to enhance the efficacy and the specificity of RNAi in experimental and potentially therapeutic settings.
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Factor 2 Eucariótico de Iniciación/metabolismo , Interferencia de ARN , Proteínas Argonautas , Sitios de Unión , Muerte Celular , Línea Celular , Receptores ErbB/metabolismo , Humanos , ARN Interferente Pequeño/metabolismoRESUMEN
The clinical efficacy of selective kinase inhibitors suggests that some cancer cells may become dependent on a single oncogene for survival. RNAi has been increasingly used to understand such "oncogene addiction" and validate new therapeutic targets. However, RNAi approaches suffer from significant off-target effects that limit their utility. Here, we combine carefully titrated lentiviral-mediated short hairpin RNA knockdown of the epidermal growth factor receptor (EGFR) with heterologous reconstitution by EGFR mutants to rigorously analyze the structural features and signaling activities that determine addiction to the mutationally activated EGFR in human lung cancer cells. EGFR dependence is differentially rescued by distinct EGFR variants and oncogenic mutants, is critically dependent on its heterodimerization partner ErbB-3, and surprisingly, does not require autophosphorylation sites in the cytoplasmic domain. Quantitative "oncogene rescue" analysis allows mechanistic dissection of oncogene addiction, and, when broadly applied, may provide functional validation for potential therapeutic targets identified through large-scale RNAi screens.
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Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/genética , Modelos Biológicos , Oncogenes/fisiología , Interferencia de ARN , Línea Celular Tumoral , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/patología , Mutación , Oncogenes/genética , ARN Interferente Pequeño/farmacología , Receptor ErbB-3RESUMEN
PURPOSE: The RET proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%-2% of non-small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating RET gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood. PATIENTS AND METHODS: We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have MET amplification associated with resistance to selpercatinib. We validated MET activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP). RESULTS: MET amplification was identified in posttreatment biopsies in 4 patients with RET fusion-positive NSCLC treated with selpercatinib. In at least one case, MET amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in RET fusion-positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months. CONCLUSIONS: Through the use of SPPs, we were able to offer combination therapy targeting MET-amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas , Ensayos Clínicos Fase I como Asunto , Crizotinib/farmacología , Crizotinib/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Amplificación de Genes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Proyectos Piloto , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-ret/genética , Pirazoles/farmacología , Pirazoles/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Resultado del TratamientoRESUMEN
Kinase inhibitors constitute an important new class of cancer drugs, whose selective efficacy is largely determined by underlying tumor cell genetics. We established a high-throughput platform to profile 500 cell lines derived from diverse epithelial cancers for sensitivity to 14 kinase inhibitors. Most inhibitors were ineffective against unselected cell lines but exhibited dramatic cell killing of small nonoverlapping subsets. Cells with exquisite sensitivity to EGFR, HER2, MET, or BRAF kinase inhibitors were marked by activating mutations or amplification of the drug target. Although most cell lines recapitulated known tumor-associated genotypes, the screen revealed low-frequency drug-sensitizing genotypes in tumor types not previously associated with drug susceptibility. Furthermore, comparing drugs thought to target the same kinase revealed striking differences, predictive of clinical efficacy. Genetically defined cancer subsets, irrespective of tissue type, predict response to kinase inhibitors, and provide an important preclinical model to guide early clinical applications of novel targeted inhibitors.
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Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Inhibidores de Proteínas Quinasas/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Ensayos de Selección de Medicamentos Antitumorales , Genotipo , Humanos , Neoplasias/genética , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Background: Anaplastic thyroid carcinoma (ATC) remains one of the most challenging malignancies to treat in the modern era. Most patients present with or develop recurrent/metastatic incurable disease with poor response rates to conventional chemotherapy, and life expectancy is short. Next-generation sequencing (NGS) can be leveraged in ATC to identify oncogenic alterations that can be targeted with molecularly specific therapy, offering new effective treatment options to a subset of patients. Patient Findings: A 73-year-old man presenting with locally advanced papillary thyroid carcinoma containing a minor component of ATC was treated with surgery and iodine-131. He developed biopsy-confirmed ATC distant metastases that progressed on cytotoxic chemotherapy. NGS revealed several alterations, including a CCDC6-RET gene fusion. The patient enrolled in LIBRETTO-001, a phase I/II trial of the potent and specific RET inhibitor, LOXO-292. The patient tolerated LOXO-292 well and experienced a deep and durable partial response, ongoing beyond 19 months. Conclusion: This clinically significant response achieved with LOXO-292 in a patient with a CCDC6-RET fusion-positive ATC who had exhausted conventional treatment options highlights the importance of conducting tumor genomic profiling in patients with ATC to identify uncommon but actionable genomic alterations, such as RET gene fusions.
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Proteínas Proto-Oncogénicas c-ret/metabolismo , Carcinoma Anaplásico de Tiroides/genética , Carcinoma Anaplásico de Tiroides/patología , Anciano , Antineoplásicos/farmacología , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Metástasis de la Neoplasia , Oncogenes , Tomografía Computarizada por Tomografía de Emisión de Positrones , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas c-ret/genética , Pirazoles/farmacología , Piridinas/farmacología , Cáncer Papilar Tiroideo/genética , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología , Resultado del TratamientoRESUMEN
INTRODUCTION: Novel rearranged in transfection (RET)-specific tyrosine kinase inhibitors (TKIs) such as selpercatinib (LOXO-292) have shown unprecedented efficacy in tumors positive for RET fusions or mutations, notably RET fusion-positive NSCLC and RET-mutated medullary thyroid cancer (MTC). However, the mechanisms of resistance to these agents have not yet been described. METHODS: Analysis was performed of circulating tumor DNA and tissue in patients with RET fusion-positive NSCLC and RET-mutation positive MTC who developed disease progression after an initial response to selpercatinib. Acquired resistance was modeled preclinically using a CCDC6-RET fusion-positive NSCLC patient-derived xenograft. The inhibitory activity of anti-RET multikinase inhibitors and selective RET TKIs was evaluated in enzyme and cell-based assays. RESULTS: After a dramatic initial response to selpercatinib in a patient with KIF5B-RET NSCLC, analysis of circulating tumor DNA revealed emergence of RET G810R, G810S, and G810C mutations in the RET solvent front before the emergence of clinical resistance. Postmortem biopsy studies reported intratumor and intertumor heterogeneity with distinct disease subclones containing G810S, G810R, and G810C mutations in multiple disease sites indicative of convergent evolution on the G810 residue resulting in a common mechanism of resistance. Acquired mutations in RET G810 were identified in tumor tissue from a second patient with CCDC6-RET fusion-positive NSCLC and in plasma from patients with additional RET fusion-positive NSCLC and RET-mutant MTC progressing on an ongoing phase 1 and 2 trial of selpercatinib. Preclinical studies reported the presence of RET G810R mutations in a CCDC6-RET patient-derived xenograft (from a patient with NSCLC) model of acquired resistance to selpercatinib. Structural modeling predicted that these mutations sterically hinder the binding of selpercatinib, and in vitro assays confirmed loss of activity for both anti-RET multikinase inhibitors and selective RET TKIs. CONCLUSIONS: RET G810 solvent front mutations represent the first described recurrent mechanism of resistance to selective RET inhibition with selpercatinib. Development of potent inhibitor of these mutations and maintaining activity against RET gatekeeper mutations could be an effective strategy to target resistance to selective RET inhibitors.
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Neoplasias Pulmonares , Proteínas Proto-Oncogénicas c-ret , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-ret/genética , Pirazoles , Piridinas , Solventes , TransfecciónRESUMEN
Medullary thyroid carcinoma (MTC) is most commonly associated with RET gene mutations. ALK fusions have rarely been described, although not previously in pediatrics and not previously partnered with CCDC6 in MTC or any other cancer. A 10-year-old boy with progressive stridor was found to have metastatic MTC, including lung, lymph node, and adrenal metastases. Baseline calcitonin was 6703 pg/mL. While molecular testing was pending, he was treated empirically with the investigational selective RET inhibitor, LOXO-292, without improvement. Molecular testing revealed a novel CCDC6-ALK fusion. His therapy was changed to crizotinib and then to alectinib for improved tolerability. Calcitonin decreased to 663 pg/mL after 6 days of ALK inhibition. He remains on alectinib with ongoing response. A novel CCDC6-ALK fusion has now been implicated in a pediatric case of metastatic MTC. This fusion has profound clinical sensitivity to ALK inhibitors. This report expands the spectrum of ALK fusions seen in MTC, including the first pediatric case of ALK translocated MTC. This novel fusion with CCDC6 has not previously been reported in other human cancers. Given the dramatic response to ALK inhibition in this case, identifying patients with ALK fusion MTC has important therapeutic implications.
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Quinasa de Linfoma Anaplásico/genética , Carcinoma Neuroendocrino/genética , Fusión Génica/genética , Neoplasias de la Tiroides/genética , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Calcitonina/metabolismo , Carbazoles/uso terapéutico , Niño , Proteínas del Citoesqueleto/genética , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Mutación , Metástasis de la Neoplasia , Piperidinas/uso terapéutico , Resultado del TratamientoRESUMEN
Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. Although responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first 2 patients with TRK fusion-positive cancers who developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.Significance: LOXO-195 abrogated resistance in TRK fusion-positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs. This establishes a role for sequential treatment by demonstrating continued TRK dependence and validates a paradigm for the accelerated development of next-generation inhibitors against validated oncogenic targets. Cancer Discov; 7(9); 963-72. ©2017 AACR.See related commentary by Parikh and Corcoran, p. 934This article is highlighted in the In This Issue feature, p. 920.
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Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor trkA/antagonistas & inhibidores , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Femenino , Humanos , Ratones , Ratones Desnudos , Células 3T3 NIH , Neoplasias/genética , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Receptor trkA/genética , Receptor trkA/metabolismoAsunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Neoplasias de la Mama/química , Femenino , Humanos , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-ret/análisis , Resultado del TratamientoAsunto(s)
Tumor Carcinoide/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Tumor Carcinoide/patología , Femenino , Humanos , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/farmacología , Piridinas/farmacología , Resultado del TratamientoRESUMEN
PURPOSE: To determine whether the selective BRAF inhibitor, dabrafenib, can stimulate radioiodine uptake in BRAF V600E-mutated unresectable or metastatic iodine-refractory papillary thyroid cancer (PTC). EXPERIMENTAL DESIGN: Ten patients with BRAF V600E-mutant iodine-refractory PTC were enrolled. Absence of radioiodine uptake on iodine-131 whole body scan obtained within 14 months of study entry was required. Each patient received dabrafenib (150 mg twice daily) for 25 days before thyrotropin α-stimulated iodine-131 whole body scan (4 mCi/148 MBq). Patients whose scan showed new sites of radioiodine uptake remained on dabrafenib for 17 more days, and then were treated with 150 mCi (5.5 GBq) iodine-131. The primary endpoint of the study was the percentage of patients with new radioiodine uptake after treatment with dabrafenib. RESULTS: Six of 10 patients (60%) demonstrated new radioiodine uptake on whole body scan after treatment with dabrafenib. All 6 were treated with 5.5 GBq iodine-131. Two patients had partial responses and 4 patients had stable disease on standard radiographic restaging at 3 months. Thyroglobulin decreased in 4 of 6 treated patients. One patient developed squamous cell carcinoma of the skin. There were no other significant adverse events attributed to dabrafenib. CONCLUSIONS: Dabrafenib can stimulate radioiodine uptake in patients with metastatic BRAF V600E-mutant iodine-refractory PTC, representing a potential new therapeutic approach for these patients.
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Carcinoma/genética , Carcinoma/patología , Diferenciación Celular/genética , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Tolerancia a Radiación/genética , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Anciano , Anciano de 80 o más Años , Carcinoma/diagnóstico , Carcinoma/metabolismo , Carcinoma/terapia , Carcinoma Papilar , Quimioradioterapia Adyuvante , Femenino , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Imidazoles/uso terapéutico , Radioisótopos de Yodo/administración & dosificación , Radioisótopos de Yodo/efectos adversos , Radioisótopos de Yodo/uso terapéutico , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Oximas/administración & dosificación , Oximas/efectos adversos , Oximas/uso terapéutico , Tiroglobulina/metabolismo , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/terapia , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Imagen de Cuerpo EnteroRESUMEN
Treatment of EGFR-mutant lung cancer with erlotinib results in dramatic tumor regression but it is invariably followed by drug resistance. In characterizing early transcriptional changes following drug treatment of mutant EGFR-addicted cells, we identified the stem cell transcriptional regulator SOX2 as being rapidly and specifically induced, both in vitro and in vivo. Suppression of SOX2 sensitizes cells to erlotinib-mediated apoptosis, ultimately decreasing the emergence of acquired resistance, whereas its ectopic expression reduces drug-induced cell death. We show that erlotinib relieves EGFR-dependent suppression of FOXO6, leading to its induction of SOX2, which in turn represses the pro-apoptotic BH3-only genes BIM and BMF. Together, these observations point to a physiological feedback mechanism that attenuates oncogene addiction-mediated cell death associated with the withdrawal of growth factor signaling and may therefore contribute to the development of resistance.
Asunto(s)
Supervivencia Celular/fisiología , Receptores ErbB/antagonistas & inhibidores , Factores de Transcripción Forkhead/fisiología , Neoplasias Pulmonares/metabolismo , Factores de Transcripción SOXB1/fisiología , Proteínas Adaptadoras Transductoras de Señales/fisiología , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/fisiología , Proteína 11 Similar a Bcl2 , Línea Celular Tumoral , Receptores ErbB/genética , Clorhidrato de Erlotinib/farmacología , Humanos , Proteínas de la Membrana/fisiología , Proteínas Proto-Oncogénicas/fisiologíaRESUMEN
BACKGROUND: With prior studies having looked at unselected cohorts, we sought to explore the mutational landscape in a high-risk group of head and neck squamous cell carcinoma (HNSCC) tumors. METHODS: A multiplexed polymerase chain reaction (PCR) assay evaluating 68 loci in 15 genes was performed on 64 patients with high-risk HNSCC. Because of the frequent PIK3CA and AKT1 mutations in patients with oropharyngeal carcinoma, we evaluated the relationship between mutation status and both clinical/pathologic variables and tumor control in this subgroup. RESULTS: Seventeen of 64 patients harbored mutations in the assayed loci: 16% in PIK3CA, 9% in TP53, 2% in AKT1, and 2% in epidermal growth factor receptor (EGFR). The frequency of PIK3CA/AKT1 mutations in oropharyngeal and sinonasal primaries was increased compared to other primary sites (35% vs 6%; p = .005). There was no relationship between mutation status and overall survival (OS), disease-specific death, or progression in the oropharyngeal cohort. CONCLUSION: We identified frequent PIK3CA mutations in patients with high-risk HNSCC confined predominantly to the oropharyngeal and sinonasal subsites; for the first time, mutation in AKT1 has been identified in HNSCC.