RESUMO
Although KRASG12C inhibitors show clinical activity in patients with KRAS G12C mutated non-small cell lung cancer (NSCLC) and other solid tumor malignancies, response is limited by multiple mechanisms of resistance. The KRASG12C inhibitor JDQ443 shows enhanced preclinical antitumor activity combined with the SHP2 inhibitor TNO155, and the combination is currently under clinical evaluation. To identify rational combination strategies that could help overcome or prevent some types of resistance, we evaluated the duration of tumor responses to JDQ443 ± TNO155, alone or combined with the PI3Kα inhibitor alpelisib and/or the cyclin-dependent kinase 4/6 inhibitor ribociclib, in xenograft models derived from a KRASG12C-mutant NSCLC line and investigated the genetic mechanisms associated with loss of response to combined KRASG12C/SHP2 inhibition. Tumor regression by single-agent JDQ443 at clinically relevant doses lasted on average 2 weeks and was increasingly extended by the double, triple, or quadruple combinations. Growth resumption was accompanied by progressively increased KRAS G12C amplification. Functional genome-wide CRISPR screening in KRASG12C-dependent NSCLC lines with distinct mutational profiles to identify adaptive mechanisms of resistance revealed sensitizing and rescuing genetic interactions with KRASG12C/SHP2 coinhibition; FGFR1 loss was the strongest sensitizer, and PTEN loss the strongest rescuer. Consistently, the antiproliferative activity of KRASG12C/SHP2 inhibition was strongly enhanced by PI3K inhibitors. Overall, KRAS G12C amplification and alterations of the MAPK/PI3K pathway were predominant mechanisms of resistance to combined KRASG12C/SHP2 inhibitors in preclinical settings. The biological nodes identified by CRISPR screening might provide additional starting points for effective combination treatments. SIGNIFICANCE: Identification of resistance mechanisms to KRASG12C/SHP2 coinhibition highlights the need for additional combination therapies for lung cancer beyond on-pathway combinations and offers the basis for development of more effective combination approaches. See related commentary by Johnson and Haigis, p. 4005.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Fosfatidilinositol 3-Quinases/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Proteínas Proto-Oncogênicas p21(ras)/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Detecção Precoce de Câncer , Inibidores Enzimáticos/uso terapêutico , Mutação , Linhagem Celular TumoralRESUMO
FGF19 signaling through the FGFR4/ß-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas, making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarized which made use of both rational and unbiased screening approaches. The optimization of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimization are improving the FGFR4 potency, metabolic stability, and solubility leading ultimately to the highly selective first-in-class clinical candidate roblitinib.
Assuntos
Piperazinas/química , Inibidores de Proteínas Quinases/química , Piridinas/química , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisteína/química , Cães , Desenho de Fármacos , Meia-Vida , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Piperazinas/metabolismo , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Ratos , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and it is the third leading cause of cancer-related deaths worldwide. Recently, aberrant signaling through the FGF19/FGFR4 axis has been implicated in HCC. Here, we describe the development of FGF401, a highly potent and selective, first in class, reversible-covalent small-molecule inhibitor of the kinase activity of FGFR4. FGF401 is exquisitely selective for FGFR4 versus the other FGFR paralogues FGFR1, FGFR2, FGFR3, and all other kinases in the kinome. FGF401 has excellent drug-like properties showing a robust pharmacokinetic/pharmacodynamics/efficacy relationship, driven by a fraction of time above the phospho-FGFR4 IC90 value. FGF401 has remarkable antitumor activity in mice bearing HCC tumor xenografts and patient-derived xenograft models that are positive for FGF19, FGFR4, and KLB. FGF401 is the first FGFR4 inhibitor to enter clinical trials, and a phase I/II study is currently ongoing in HCC and other solid malignancies.
Assuntos
Fatores de Crescimento de Fibroblastos/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Animais , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , Transdução de SinaisRESUMO
The fibroblast growth factor (FGF) signaling cascade is a key signaling pathway in hepatocarcinogenesis. We report high FGF receptor (FGFR) expression in 17.7% (11 of 62) of hepatocellular carcinoma (HCC) models. Infigratinib, a pan-FGFR inhibitor, potently suppresses the growth of high-FGFR-expressing and sorafenib-resistant HCCs. Infigratinib inhibits FGFR signaling and its downstream targets, cell proliferation, the angiogenic rescue program, hypoxia, invasion, and metastasis. Infigratinib also induces apoptosis and vessel normalization and improves the overall survival of mice bearing FGFR-driven HCCs. Infigratinib acts in synergy with the microtubule-depolymerizing drug vinorelbine to promote apoptosis, suppress tumor growth, and improve the overall survival of mice. Increased expression levels of FGFR-2 and FGFR-3 through gene amplification correlate with treatment response and may serve as potential biomarkers for patient selection. Conclusion: Treatments with Infigratinib alone or in combination with vinorelbine may be effective in a subset of patients with HCC with FGFR-driven tumors.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Pirimidinas/uso terapêutico , Animais , Vasos Sanguíneos/efeitos dos fármacos , Carcinoma Hepatocelular/secundário , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos SCID , Compostos de Fenilureia/farmacologia , Pirimidinas/farmacologiaRESUMO
PURPOSE: Concurrent PIK3CA mutations and fibroblast growth factor receptor (FGFR) alterations occur in multiple cancer types, including estrogen receptor-positive breast cancer, bladder cancer, and endometrial cancer. In this first-in-human combination trial, we explored safety and preliminary efficacy of combining the PI3Kα selective inhibitor alpelisib with the FGFR1-4 selective inhibitor infigratinib. PATIENTS AND METHODS: Patients with PIK3CA-mutant advanced solid tumors, with or without FGFR1-3 alterations, were enrolled in the dose escalation or one of three molecular-defined dose-expansion cohorts. The primary end point was the maximum tolerated dose. Secondary end points included safety, pharmacokinetics, and response. Archival tumor samples were sequenced to explore genomic correlates of response. RESULTS: In combination, both agents were escalated to full, single-agent recommended doses (alpelisib, 300 mg per day continuously; infigratinib, 125 mg per day 3 weeks on followed by 1 week off). The toxicity profile of the combination was consistent with the established safety profile of each agent, although 71% of all patients required at least one treatment interruption or dose reduction. Molecularly selected dose expansions in breast cancer and other solid tumors harboring PIK3CA mutations, alone or in combination with FGFR alterations, identified sporadic responses, predominately in tumor types and genotypes previously defined to have sensitivity to these agents. CONCLUSION: The combination of alpelisib and infigratinib can be administered at full single-agent doses, although the high rate of dose interruption or reduction suggests long-term tolerability may be challenging. In exploratory signal-seeking cohorts of patients harboring dual PIK3CA and FGFR1-3 alterations, no clear evidence of synergistic activity was observed.
RESUMO
BGJ398, a potent and selective pan-FGFR antagonist, was prospectively evaluated in patients with metastatic urothelial carcinoma bearing a diverse array of FGFR3 alterations. Patients (N = 67) who were unable to receive platinum chemotherapy were enrolled. The majority (70.1%) had received two or more prior antineoplastic therapies. BGJ398 was administered orally at 125 mg/day on a 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. The primary endpoint was the response rate. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%. The most common treatment-emergent toxicities were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite. Further examination of BGJ398 in this disease setting is warranted.Significance: BJG398 is active in patients with alterations in FGFR3, resulting in both reductions in tumor volume and stabilization of disease. Our data highlight putative mechanisms of resistance to the agent, which may be useful in following disease status. Cancer Discov; 8(7); 812-21. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 781.
Assuntos
Mutação , Compostos de Fenilureia/uso terapêutico , Pirimidinas/uso terapêutico , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Neoplasias Urológicas/tratamento farmacológico , Administração Oral , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Resultado do Tratamento , Neoplasias Urológicas/metabolismoRESUMO
The FGF19- fibroblast growth factor receptor (FGFR4)-ßKlotho (KLB) pathway plays an important role in the regulation of bile acid (BA) homeostasis. Aberrant activation of this pathway has been described in the development and progression of a subset of liver cancers including hepatocellular carcinoma, establishing FGFR4 as an attractive therapeutic target for such solid tumors. FGF401 is a highly selective FGFR4 kinase inhibitor being developed for hepatocellular carcinoma, currently in phase I/II clinical studies. In preclinical studies in mice and dogs, oral administration of FGF401 led to induction of Cyp7a1, elevation of its peripheral marker 7alpha-hydroxy-4-cholesten-3-one, increased BA pool size, decreased serum cholesterol and diarrhea in dogs. FGF401 was also associated with increases of serum aminotransferases, primarily alanine aminotransferase (ALT), in the absence of any observable adverse histopathological findings in the liver, or in any other organs. We hypothesized that the increase in ALT could be secondary to increased BAs and conducted an investigative study in dogs with FGF401 and coadministration of the BA sequestrant cholestyramine (CHO). CHO prevented and reversed FGF401-related increases in ALT in dogs in parallel to its ability to reduce BAs in the circulation. Correlation analysis showed that FGF401-mediated increases in ALT strongly correlated with increases in taurolithocholic acid and taurodeoxycholic acid, the major secondary BAs in dog plasma, indicating a mechanistic link between ALT elevation and changes in BA pool hydrophobicity. Thus, CHO may offer the potential to mitigate elevations in serum aminotransferases in human subjects that are caused by targeted FGFR4 inhibition and elevated intracellular BA levels.
Assuntos
Alanina Transaminase/sangue , Ácidos e Sais Biliares/sangue , Resina de Colestiramina/farmacologia , Fígado/efeitos dos fármacos , Inibidores de Proteínas Quinases/toxicidade , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Alanina Transaminase/biossíntese , Animais , Ácidos e Sais Biliares/biossíntese , Cães , Relação Dose-Resposta a Droga , Feminino , Fígado/enzimologia , Masculino , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/sangue , Piridinas/farmacologia , Testes de Toxicidade , ToxicocinéticaRESUMO
Purpose This two-part, first-in-human study was initiated in patients with advanced solid tumors harboring genetic alterations in fibroblast growth factor receptors (FGFRs) to determine the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of oral BGJ398, a selective FGFR1-3 tyrosine kinase inhibitor. Patients and Methods Adult patients were treated with escalating dosages of BGJ398 5 to 150 mg once daily or 50 mg twice daily continuously in 28-day cycles. During expansion at the MTD, patients with FGFR1-amplified squamous cell non-small-cell lung cancer (sqNSCLC; arm 1) or other solid tumors with FGFR genetic alterations (mutations/amplifications/fusions) received BGJ398 daily on a continuous schedule (arm 2), or on a 3-weeks-on/1-week-off schedule (arm 3). Results Data in 132 patients from the escalation and expansion arms are reported (May 15, 2015, cutoff). The MTD, 125 mg daily, was determined on the basis of dose-limiting toxicities in four patients (100 mg, grade 3 aminotransferase elevations [n = 1]; 125 mg, hyperphosphatemia [n = 1]; 150 mg, grade 1 corneal toxicity [n = 1] and grade 3 aminotransferase elevations [n = 1]). Common adverse events in patients treated at the MTD (n = 57) included hyperphosphatemia (82.5%), constipation (50.9%), decreased appetite (45.6%), and stomatitis (45.6%). A similar safety profile was observed using the 3-weeks-on/1-week-off schedule (RP2D). However, adverse event-related dose adjustments/interruptions were less frequent with the 3-weeks-on/1-week-off (50.0%) versus the continuous (73.7%) schedule. Antitumor activity (seven partial responses [six confirmed]) was demonstrated with BGJ398 doses ≥ 100 mg in patients with FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancer. Conclusion BGJ398 at the MTD/RP2D had a tolerable and manageable safety profile and showed antitumor activity in several tumor types, including FGFR1-amplified sqNSCLC and FGFR3-mutant bladder/urothelial cancers.
Assuntos
Antineoplásicos/administração & dosagem , Compostos de Fenilureia/administração & dosagem , Pirimidinas/administração & dosagem , Receptores de Fatores de Crescimento de Fibroblastos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Feminino , Humanos , Hiperfosfatemia/induzido quimicamente , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/sangue , Compostos de Fenilureia/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/sangue , Pirimidinas/farmacocinéticaRESUMO
A diverse range of selective FGFR4 inhibitor hit series were identified using unbiased screening approaches and by the modification of known kinase inhibitor scaffolds. In each case the origin of the selectivity was consistent with an interaction with a poorly conserved cysteine residue within the middle-hinge region of the kinase domain of FGFR4, at position 552. Targeting this region identified a non-covalent diaminopyrimidine series differentiating by size, an irreversible-covalent inhibitor in which Cys552 undergoes an SNAr reaction with a 2-chloropyridine, and a reversible-covalent inhibitor series in which Cys552 forms a hemithioacetal adduct with a 2-formyl naphthalene. In addition, the introduction of an acrylamide into a known FGFR scaffold identified a pan-FGFR inhibitor which reacted with both Cys552 and a second poorly conserved cysteine on the P-loop of FGFR4 at position 477 which is present in all four FGFR family members.
RESUMO
Achondroplasia (ACH) is the most frequent form of dwarfism and is caused by gain-of-function mutations in the fibroblast growth factor receptor 3-encoding (FGFR3-encoding) gene. Although potential therapeutic strategies for ACH, which aim to reduce excessive FGFR3 activation, have emerged over many years, the use of tyrosine kinase inhibitor (TKI) to counteract FGFR3 hyperactivity has yet to be evaluated. Here, we have reported that the pan-FGFR TKI, NVP-BGJ398, reduces FGFR3 phosphorylation and corrects the abnormal femoral growth plate and calvaria in organ cultures from embryos of the Fgfr3Y367C/+ mouse model of ACH. Moreover, we demonstrated that a low dose of NVP-BGJ398, injected subcutaneously, was able to penetrate into the growth plate of Fgfr3Y367C/+ mice and modify its organization. Improvements to the axial and appendicular skeletons were noticeable after 10 days of treatment and were more extensive after 15 days of treatment that started from postnatal day 1. Low-dose NVP-BGJ398 treatment reduced intervertebral disc defects of lumbar vertebrae, loss of synchondroses, and foramen-magnum shape anomalies. NVP-BGJ398 inhibited FGFR3 downstream signaling pathways, including MAPK, SOX9, STAT1, and PLCγ, in the growth plates of Fgfr3Y367C/+ mice and in cultured chondrocyte models of ACH. Together, our data demonstrate that NVP-BGJ398 corrects pathological hallmarks of ACH and support TKIs as a potential therapeutic approach for ACH.
Assuntos
Acondroplasia/tratamento farmacológico , Condrócitos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Pirimidinas/farmacologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Acondroplasia/genética , Acondroplasia/metabolismo , Acondroplasia/patologia , Animais , Linhagem Celular Transformada , Condrócitos/patologia , Modelos Animais de Doenças , Células HEK293 , Humanos , Disco Intervertebral/metabolismo , Disco Intervertebral/patologia , Vértebras Lombares/metabolismo , Vértebras Lombares/patologia , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Mutantes , Fosfolipase C gama/genética , Fosfolipase C gama/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismoRESUMO
Biomarkers for patient selection are essential for the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study, we report the discovery of a novel patient selection strategy for the p53-HDM2 inhibitor NVP-CGM097, currently under evaluation in clinical trials. By intersecting high-throughput cell line sensitivity data with genomic data, we have identified a gene expression signature consisting of 13 up-regulated genes that predicts for sensitivity to NVP-CGM097 in both cell lines and in patient-derived tumor xenograft models. Interestingly, these 13 genes are known p53 downstream target genes, suggesting that the identified gene signature reflects the presence of at least a partially activated p53 pathway in NVP-CGM097-sensitive tumors. Together, our findings provide evidence for the use of this newly identified predictive gene signature to refine the selection of patients with wild-type p53 tumors and increase the likelihood of response to treatment with p53-HDM2 inhibitors, such as NVP-CGM097.
Assuntos
Biomarcadores/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Isoquinolinas/farmacologia , Neoplasias/tratamento farmacológico , Seleção de Pacientes , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Linhagem Celular Tumoral , Transferência Ressonante de Energia de Fluorescência , Perfilação da Expressão Gênica , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Malignant rhabdoid tumors (MRTs) are aggressive pediatric cancers arising in brain, kidney and soft tissues, which are characterized by loss of the tumor suppressor SNF5/SMARCB1. MRTs are poorly responsive to chemotherapy and thus a high unmet clinical need exists for novel therapies for MRT patients. SNF5 is a core subunit of the SWI/SNF chromatin remodeling complex which affects gene expression by nucleosome remodeling. Here, we report that loss of SNF5 function correlates with increased expression of fibroblast growth factor receptors (FGFRs) in MRT cell lines and primary tumors and that re-expression of SNF5 in MRT cells causes a marked repression of FGFR expression. Conversely, siRNA-mediated impairment of SWI/SNF function leads to elevated levels of FGFR2 in human fibroblasts. In vivo, treatment with NVP-BGJ398, a selective FGFR inhibitor, blocks progression of a murine MRT model. Hence, we identify FGFR signaling as an aberrantly activated oncogenic pathway in MRTs and propose pharmacological inhibition of FGFRs as a potential novel clinical therapy for MRTs.
Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Tumor Rabdoide/metabolismo , Fatores de Transcrição/metabolismo , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Montagem e Desmontagem da Cromatina/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Fibroblastos/metabolismo , Células HEK293 , Humanos , Camundongos , Regiões Promotoras Genéticas/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Tumor Rabdoide/genética , Proteína SMARCB1 , Transdução de Sinais/genética , Fatores de Transcrição/genéticaRESUMO
Fibroblast growth factor 23 (FGF23) is a circulating factor secreted by osteocytes that is essential for phosphate homeostasis. In kidney proximal tubular cells FGF23 inhibits phosphate reabsorption and leads to decreased synthesis and enhanced catabolism of 1,25-dihydroxyvitamin D3 (1,25[OH]2 D3 ). Excess levels of FGF23 cause renal phosphate wasting and suppression of circulating 1,25(OH)2 D3 levels and are associated with several hereditary hypophosphatemic disorders with skeletal abnormalities, including X-linked hypophosphatemic rickets (XLH) and autosomal recessive hypophosphatemic rickets (ARHR). Currently, therapeutic approaches to these diseases are limited to treatment with activated vitamin D analogues and phosphate supplementation, often merely resulting in partial correction of the skeletal aberrations. In this study, we evaluate the use of FGFR inhibitors for the treatment of FGF23-mediated hypophosphatemic disorders using NVP-BGJ398, a novel selective, pan-specific FGFR inhibitor currently in Phase I clinical trials for cancer therapy. In two different hypophosphatemic mouse models, Hyp and Dmp1-null mice, resembling the human diseases XLH and ARHR, we find that pharmacological inhibition of FGFRs efficiently abrogates aberrant FGF23 signaling and normalizes the hypophosphatemic and hypocalcemic conditions of these mice. Correspondingly, long-term FGFR inhibition in Hyp mice leads to enhanced bone growth, increased mineralization, and reorganization of the disturbed growth plate structure. We therefore propose NVP-BGJ398 treatment as a novel approach for the therapy of FGF23-mediated hypophosphatemic diseases.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Compostos de Fenilureia/farmacologia , Pirimidinas/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Raquitismo Hipofosfatêmico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Desenvolvimento Ósseo/efeitos dos fármacos , Proteínas da Matriz Extracelular/deficiência , Proteínas da Matriz Extracelular/metabolismo , Fêmur/efeitos dos fármacos , Fêmur/patologia , Fator de Crescimento de Fibroblastos 23 , Lâmina de Crescimento/efeitos dos fármacos , Lâmina de Crescimento/patologia , Homeostase/efeitos dos fármacos , Íons , Rim/efeitos dos fármacos , Rim/metabolismo , Camundongos Endogâmicos C57BL , Minerais/metabolismo , Compostos de Fenilureia/uso terapêutico , Pirimidinas/uso terapêutico , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Raquitismo Hipofosfatêmico/tratamento farmacológico , Raquitismo Hipofosfatêmico/patologia , Cauda/anatomia & histologia , Vitamina D/análogos & derivados , Vitamina D/biossínteseRESUMO
UNLABELLED: Patient stratification biomarkers that enable the translation of cancer genetic knowledge into clinical use are essential for the successful and rapid development of emerging targeted anticancer therapeutics. Here, we describe the identification of patient stratification biomarkers for NVP-BGJ398, a novel and selective fibroblast growth factor receptor (FGFR) inhibitor. By intersecting genome-wide gene expression and genomic alteration data with cell line-sensitivity data across an annotated collection of cancer cell lines called the Cancer Cell Line Encyclopedia, we show that genetic alterations for FGFR family members predict for sensitivity to NVP-BGJ398. For the first time, we report oncogenic FGFR1 amplification in osteosarcoma as a potential patient selection biomarker. Furthermore, we show that cancer cell lines harboring FGF19 copy number gain at the 11q13 amplicon are sensitive to NVP-BGJ398 only when concomitant expression of ß-klotho occurs. Thus, our findings provide the rationale for the clinical development of FGFR inhibitors in selected patients with cancer harboring tumors with the identified predictors of sensitivity. SIGNIFICANCE: The success of a personalized medicine approach using targeted therapies ultimately depends on being able to identify the patients who will benefit the most from any given drug. To this end, we have integrated the molecular profiles for more than 500 cancer cell lines with sensitivity data for the novel anticancer drug NVP-BGJ398 and showed that FGFR genetic alterations are the most significant predictors for sensitivity. This work has ultimately endorsed the incorporation of specific patient selection biomakers in the clinical trials for NVP-BGJ398.
Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Compostos de Fenilureia/farmacologia , Pirimidinas/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/genética , Animais , Linhagem Celular Tumoral , Amplificação de Genes/efeitos dos fármacos , Células HEK293 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Camundongos , Modelos Moleculares , Neoplasias/genética , Neoplasias/patologia , Compostos de Fenilureia/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The overall power of kinase inhibitors is substantially overshadowed by the acquisition of drug resistance. To address this issue, we systematically assessed the potential of secreted proteins to induce resistance to kinase inhibitors. To this end, we developed a high-throughput platform for screening a cDNA library encoding 3,432 secreted proteins in cellular assays. Using cancer cells originally dependent on either MET, FGFR2, or FGFR3, we observed a bypass of dependence through ligand-mediated activation of alternative receptor tyrosine kinases (RTK). Our findings indicate a broad and versatile potential for RTKs from the HER and FGFR families as well as MET to compensate for loss of each other. We further provide evidence that combined inhibition of simultaneously active RTKs can lead to an added anticancer effect.
Assuntos
Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor ErbB-2/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/genética , Transdução de Sinais/efeitos dos fármacos , Transplante HeterólogoRESUMO
A novel series of N-aryl-N'-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the fibroblast growth factor receptor tyrosine kinases 1, 2, and 3 by rationally designing the substitution pattern of the aryl ring. On the basis of its in vitro profile, compound 1h (NVP-BGJ398) was selected for in vivo evaluation and showed significant antitumor activity in RT112 bladder cancer xenografts models overexpressing wild-type FGFR3. These results support the potential therapeutic use of 1h as a new anticancer agent.
Assuntos
Antineoplásicos/síntese química , Compostos de Fenilureia/síntese química , Pirimidinas/síntese química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Transplante de Neoplasias , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Wistar , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Relação Estrutura-Atividade , Transplante Heterólogo , Neoplasias da Bexiga UrináriaRESUMO
We have previously shown that mice with a CNS restricted knock-out of the integrin beta1 subunit gene (Itgb1-CNSko mice) have defects in the formation of lamina and folia in the cerebral and cerebellar cortices that are caused by disruption of the cortical marginal zones. Cortical structures in postnatal and adult Itgb1-CNSko animals are also reduced in size, but the mechanism that causes the size defect has remained unclear. We now demonstrate that proliferation of granule cell precursors (GCPs) is severely affected in the developing cerebellum of Itgb1-CNSko mice. In the absence of beta1 expression, GCPs lose contact with laminin in the meningeal basement membrane, cease proliferating, and differentiate prematurely. In vitro studies provide evidence that beta1 integrins act at least in part cell autonomously in GCPs to regulate their proliferation. Previous studies have shown that sonic hedgehog (Shh)-induced GCP proliferation is potentiated by the integrin ligand laminin. We show that Shh directly binds to laminin and that laminin-Shh induced cell proliferation is dependent on beta1 integrin expression in GCPs. Taken together, these data are consistent with a model in which beta1 integrin expression in GCPs is required to recruit a laminin-Shh complex to the surface of GCPs and to subsequently modulate the activity of signaling pathways that regulate proliferation.