RESUMEN

Pyruvate dehydrogenase kinases (PDKs) are serine/threonine kinases, that are directly involved in altered cancer cell metabolism, resulting in cancer aggressiveness and resistance. Dichloroacetic acid (DCA) is the first PDK inhibitor that has entered phase II clinical; however, several side effects associated with weak anticancer activity and excessive drug dose (100 mg/kg) have led to its limitation in clinical application. Building upon a molecular hybridization approach, a small library of 3-amino-1,2,4-triazine derivatives has been designed, synthesized, and characterized for their PDK inhibitory activity using in silico, in vitro, and in vivo assays. Biochemical screenings showed that all synthesized compounds are potent and subtype-selective inhibitors of PDK. Accordingly, molecular modeling studies revealed that a lot of ligands can be properly placed inside the ATP-binding site of PDK1. Interestingly, 2D and 3D cell studies revealed their ability to induce cancer cell death at low micromolar doses, being extremely effective against human pancreatic KRAS mutated cancer cells. Cellular mechanistic studies confirm their ability to hamper the PDK/PDH axis, thus leading to metabolic/redox cellular impairment, and to ultimately trigger apoptotic cancer cell death. Remarkably, preliminary in vivo studies performed on a highly aggressive and metastatic Kras-mutant solid tumor model confirm the ability of the most representative compound 5i to target the PDH/PDK axis in vivo and highlighted its equal efficacy and better tolerability profile with respect to those elicited by the reference FDA approved drugs, cisplatin and gemcitabine. Collectively, the data highlights the promising anticancer potential of these novel PDK-targeting derivatives toward obtaining clinical candidates for combatting highly aggressive KRAS-mutant pancreatic ductal adenocarcinomas.

Asunto(s)

Adenocarcinoma , Neoplasias Pancreáticas , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Bibliotecas de Moléculas Pequeñas , Humanos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias Pancreáticas

RESUMEN

Since its discovery as the first human oncogene in 1983, the small GTPase KRAS has been a major target of cancer drug discovery. The paper reported in this issue describes a long-awaited small molecule drug candidate of the oncogenic KRAS (G12D) mutant for the treatment of currently incurable pancreatic cancer.

Asunto(s)

Antineoplásicos/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/genética , Alelos , Animales , Descubrimiento de Drogas , Regulación Neoplásica de la Expresión Génica , Humanos , Mutación

RESUMEN

BACKGROUND: Statins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRASmut) tumors. METHODS: The immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRASmut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment. RESULTS: Statin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRASmut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRASmut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRASmut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRASmut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRASmut tumor models. CONCLUSIONS: Our findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity.

Asunto(s)

Estrés del Retículo Endoplásmico/genética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Animales , Humanos , Masculino , Ratones , Mutación , Transfección

RESUMEN

Saffron has been applied in depression treatment, but its antidepressant compounds and mechanisms are unclear. In this research, a network pharmacology-based method was proposed to screen the active compounds and the potential mechanisms of saffron for depression treatment. Firstly, the chemical compounds of saffron were collected from literature and filtered by drug-like prediction. Secondly, common targets, by comparing the targets of saffron predicted by Pharm Mapper server with targets associated with depression collected from Genecards, were regarded as the antidepressant targets of saffron. Thirdly, common targets were mapped to KEGG pathways, considered as the pathways related with the antidepressant effects of saffron. Finally, the network of compounds-targets-pathways was constructed and analyzed by cytoscape 3.4.0. Ten compounds including crocetin, picrocrocin, (1R, 5S, 6R)-5-(hydroxymethyl)- 4, 4, 6-trimethyl-7-Oxabicyclo[4.1.0]heptan-2-one and its glycoside were screened as the main antidepressant compounds, some of which were reported for the first time. They might have effective treatment for depression by acting on targets, such as MAP2K1, MAPK1, HRAS, PIK3R1, ALB and AKT1 and pathways related with immune system, signal transduction and so on. This study provided a new insight into the antidepressant mechanism and active compounds of saffron, which also had a guiding effect on later experiments.

Asunto(s)

Antidepresivos/farmacología , Crocus/química , Flores , Farmacología en Red , Albúminas/efectos de los fármacos , Albúminas/metabolismo , Carotenoides/química , Fosfatidilinositol 3-Quinasa Clase Ia/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Ciclohexenos/química , Glucósidos/química , Humanos , MAP Quinasa Quinasa 1/efectos de los fármacos , MAP Quinasa Quinasa 1/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/efectos de los fármacos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Transducción de Señal/efectos de los fármacos , Terpenos/química , Vitamina A/análogos & derivados , Vitamina A/química

RESUMEN

Pancreatic cancer is among the most refractory malignancies with poor prognosis. Thus, preventive approaches, in addition to the development of novel therapeutic strategies are essential for this type of cancer. KRAS mutations occur very early in the development of pancreatic cancers and could be targeted for its prevention, yet specific inhibitors for mutated KRAS are lacking. Accordingly, Glutathione-S Transferase p1 (GSTP1), which we recently found to be an autocrine stimulator of mutated KRAS signaling, is predicted to be an alternative target for chemoprevention of pancreatic cancer. In this study, chemopreventive effects of O-Hexadecyl-γ-glutamyl-S-benzyl-cysteinyl-D-phenyl glycine-Ethylester (HGBPE), which we previously synthesized to inhibit GSTP1 activity, was analyzed for its effect on the prevention of a rat pancreatic carcinogenesis model induced by 7,12-dimethyl-benzanthracene (DMBA). Rats administered with DMBA were grouped into five cohorts. In the treated group I, which was treated neither with HGBPE nor vehicle, sequential appearance of precancerous lesions, ductal complexes, and adenocarcinoma was confirmed as previously reported. We also confirmed in this group that mutations of KRAS and expression of GSTP1 simultaneously occurred in the ductal complex. To rats of groups II and IV, HGBPE was administered, and vehicle to those of group III and V. In groups of II and IV, the incidence of both ductal complex and adenocarcinoma were significantly lower than those in groups III and V. These data clearly suggest the efficacy of HGBP as a potential chemopreventive agent for pancreatic cancer.

Asunto(s)

Gutatión-S-Transferasa pi/farmacología , Neoplasias Pancreáticas/prevención & control , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , 9,10-Dimetil-1,2-benzantraceno/farmacología , Animales , Modelos Animales de Enfermedad , Neoplasias Pancreáticas/inducido químicamente , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos

RESUMEN

KRAS mutations drive a wide variety of cancers. Drugs targeting the protein product of KRASG12C mutations are currently being evaluated show preliminary efficacy in clinical trials. A clinical trial of VS-6766, a dual RAF-MEK inhibitor, has reported early single agent activity in non-G12C mutated KRAS driven cancers.

Asunto(s)

Neoplasias/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas p21(ras)/genética , Humanos , Terapia Molecular Dirigida , Mutación , Neoplasias/tratamiento farmacológico , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/metabolismo

RESUMEN

PURPOSE OF REVIEW: Mutations in kirsten rat sarcoma viral oncogene homolog (KRAS) are the most frequently observed genomic alterations in human cancers. No KRAS targeting therapy has been approved despite more than three decades of efforts. Encouraging progress has been made in targeting KRASG12C with KRASG12C specific covalent inhibitors in the past few years. Herein, we review the recent breakthroughs in KRAS targeting. RECENT FINDINGS: KRASG12C mutation was found in 14% of non-small cell lung cancer (NSCLC) and 3% of colorectal cancer. Recently, highly potent KRASG12C specific inhibitors have been developed and demonstrated potent activity in preclinical models. Early results from phase 1 clinical trials with sotorasib and MRTX849 show promising antitumor activity in NSCLC, colorectal cancer and other solid tumors harboring KRASG12C mutation. For the first time, the preclinical success of targeting KRAS has translated into clinical benefits, which holds the potential of transforming clinical management of KRAS mutated solid tumors. Additional efforts are needed to identify biomarkers that predict response to KRAS inhibition in patients with KRASG12C as well as to develop strategies to overcome resistance.

Asunto(s)

Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Humanos , Neoplasias Pulmonares/tratamiento farmacológico

RESUMEN

Aberrations in rat sarcoma (RAS) viral oncogene are the most prevalent and best-known genetic alterations identified in human cancers. Indeed, RAS drives tumorigenesis as one of the downstream effectors of EGFR activation, regulating cellular switches and functions and triggering intracellular signaling cascades such as the MAPK and PI3K pathways. Of the three RAS isoforms expressed in human cells, all of which were linked to tumorigenesis more than three decades ago, KRAS is the most frequently mutated. In particular, point mutations in KRAS codon 12 are present in up to 80% of KRAS-mutant malignancies. Unfortunately, there are no approved KRAS-targeted agents, despite decades of research and development. Recently, a revolutionary strategy to use covalent allosteric inhibitors that target a shallow pocket on the KRAS surface has provided new impetus for renewed drug development efforts, specifically against KRASG12C. These inhibitors, such as AMG 510 and MRTX849, show promise in early-phase studies. Nevertheless, combination strategies that target resistance mechanisms have become vital in the war against KRAS-mutant tumors.

Asunto(s)

Acetonitrilos/farmacología , Transformación Celular Neoplásica/genética , ADN de Neoplasias/genética , Mutación , Neoplasias/tratamiento farmacológico , Piperazinas/farmacología , Proteínas Proto-Oncogénicas p21(ras)/genética , Piridinas/farmacología , Pirimidinas/farmacología , Antineoplásicos/farmacología , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos

RESUMEN

CDK4/cyclin D kinase constitutes an attractive pharmacological target for development of anticancer therapeutics, in particular in KRAS-mutant lung cancer patients, who have a poor prognosis and no targeted therapy available yet. Although several ATP-competitive inhibitors of CDK4 have been developed for anticancer therapeutics, they suffer from limited specificity and efficacy. Methods: As an alternative to ATP-competitive inhibitors we have designed a stapled peptide to target the main interface between CDK4 and cyclin D, and have characterized its physico-chemical properties and affinity to bind cyclin D1. Results: We have validated a positive correlation between CDK4/cyclin D level and KRAS mutation in lung cancer patients. The stapled peptide enters cells rapidly and efficiently, and inhibits CDK4 kinase activity and proliferation in lung cancer cells. Its intrapulmonary administration in mice enables its retention in orthotopic lung tumours and complete inhibition of their growth when co-administered with Abemaciclib. Conclusion: The stapled peptide targeting the main interface between CDK4 and cyclin D provides promising therapeutic perspectives for patients with lung cancer.

Asunto(s)

Aminopiridinas/farmacología , Bencimidazoles/farmacología , Ciclina D/metabolismo , Quinasa 4 Dependiente de la Ciclina/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Péptidos/farmacología , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Aminopiridinas/administración & dosificación , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Bencimidazoles/administración & dosificación , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Humanos , Neoplasias Pulmonares/genética , Ratones , Ratones Desnudos , Mutación , Imagen Óptica/métodos , Péptidos/administración & dosificación , Péptidos/química , Proteínas Proto-Oncogénicas p21(ras)/metabolismo

RESUMEN

Cancers of nearly all lineages harbor alterations that deregulate mitogen-activated protein kinase signaling, a crucial signaling pathway for tumor formation and maintenance. Of these, KRAS mutations are the most frequent gain-of-function alterations found in patients with cancer. In particular they represents the most common molecular alteration detected in non-small cell lung cancer (NSCLC) accounting for up to 25% of all oncogenic mutations. They were identified decades ago and prior efforts to target these proteins have been unsuccessful. KRAS mutation profiles (i.e. frequency of specific codon substitutions) in smokers and never-smokers are distinct and not all KRAS alterations are driver mutations. KRAS has evolved from a mutation with possible predictive value to a therapeutic target with great promise. Here, we will discuss the biology of KRAS in lung cancer and its clinical implications in oncology today and in the foreseeable future.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas p21(ras)/genética , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Predicción , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunoterapia/métodos , Neoplasias Pulmonares/mortalidad , Masculino , Mutación , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Análisis de Supervivencia , Resultado del Tratamiento

RESUMEN

Pancreatic cancer is a highly aggressive malignancy that strongly resists extant treatments. The failure of existing therapies is majorly attributed to the tough tumor microenvironment (TME) limiting drug access and the undruggable targets of tumor cells. The formation of suppressive TME is regulated by transforming growth factor beta (TGF-ß) signaling, while the poor response and short survival of almost 90% of pancreatic cancer patients results from the oncogenic KRAS mutation. Hence, simultaneously targeting both the TGF-ß and KRAS pathways might dismantle the obstacles of pancreatic cancer therapy. Here, a novel sequential-targeting strategy is developed, in which antifibrotic fraxinellone-loaded CGKRK-modified nanoparticles (Frax-NP-CGKRK) are constructed to regulate TGF-ß signaling and siRNA-loaded lipid-coated calcium phosphate (LCP) biomimetic nanoparticles (siKras-LCP-ApoE3) are applied to interfere with the oncogenic KRAS. Frax-NP-CGKRK successfully targets the tumor sites through the recognition of overexpressed heparan sulfate proteoglycan, reverses the activated cancer-associated fibroblasts (CAFs), attenuates the dense stroma barrier, and enhances tumor blood perfusion. Afterward, siKras-LCP-ApoE3 is efficiently internalized by the tumor cells through macropinocytosis and specifically silencing KRAS mutation. Compared with gemcitabine, this sequential-targeting strategy significantly elongates the lifespans of pancreatic tumor-bearing animals, hence providing a promising approach for pancreatic cancer therapy.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzofuranos/administración & dosificación , Terapia Molecular Dirigida/métodos , Neoplasias Pancreáticas/tratamiento farmacológico , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , ARN Interferente Pequeño/administración & dosificación , Factor de Crecimiento Transformador beta/efectos de los fármacos , Animales , Apolipoproteína E3/genética , Esquema de Medicación , Portadores de Fármacos/administración & dosificación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Ratones Desnudos , Mutación/efectos de los fármacos , Células 3T3 NIH , Nanopartículas/administración & dosificación , Neoplasias Pancreáticas/patología , Fragmentos de Péptidos/administración & dosificación , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/genética , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Targeting KRAS mutant tumors through inhibition of individual downstream pathways has had limited clinical success. Here we report that RAF inhibitors exhibit little efficacy in KRAS mutant tumors. In combination drug screens, MEK and PI3K inhibitors synergized with pan-RAF inhibitors through an RAS-GTP-dependent mechanism. Broad cell line profiling with RAF/MEK inhibitor combinations revealed synergistic efficacy in KRAS mutant and wild-type tumors, with KRASG13D mutants exhibiting greater synergy versus KRASG12 mutant tumors. Mechanistic studies demonstrate that MEK inhibition induced RAS-GTP levels, RAF dimerization and RAF kinase activity resulting in MEK phosphorylation in synergistic tumor lines regardless of KRAS status. Taken together, our studies uncover a strategy to rewire KRAS mutant tumors to confer sensitivity to RAF kinase inhibition.

Asunto(s)

Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Línea Celular Tumoral , Guanosina Trifosfato/metabolismo , Humanos , Mutación/efectos de los fármacos , Mutación/genética , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas B-raf/efectos de los fármacos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas ras/efectos de los fármacos , Proteínas ras/genética

RESUMEN

The majority of US adult cancer patients today are diagnosed and treated outside the context of any clinical trial (that is, in the real world). Although these patients are not part of a research study, their clinical data are still recorded. Indeed, data captured in electronic health records form an ever-growing, rich digital repository of longitudinal patient experiences, treatments, and outcomes. Likewise, genomic data from tumor molecular profiling are increasingly guiding oncology care. Linking real-world clinical and genomic data, as well as information from other co-occurring data sets, could create study populations that provide generalizable evidence for precision medicine interventions. However, the infrastructure required to link, ensure quality, and rapidly learn from such composite data is complex. We outline the challenges and describe a novel approach to building a real-world clinico-genomic database of patients with cancer. This work represents a case study in how data collected during routine patient care can inform precision medicine efforts for the population at large. We suggest that health policies can promote innovation by defining appropriate uses of real-world evidence, establishing data standards, and incentivizing data sharing.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Difusión de la Información , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Registros Electrónicos de Salud , Femenino , Estudios de Seguimiento , Genómica , Humanos , Terapia Molecular Dirigida , Pronóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Sirolimus/análogos & derivados , Sirolimus/uso terapéutico , Resultado del Tratamiento

RESUMEN

BACKGROUND: The efficacy of oxaliplatin-based chemotherapy combined with anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) remains controversial in metastatic colorectal cancer (mCRC). This meta-analysis aims to estimate the effect of adding panitumumab or cetuximab to oxaliplatin-based chemotherapy in RAS wild type mCRC patients for the first-line treatment. The primary tumor location is also considered into this meta-analysis. METHODS: RCT studies were identified by a search of MEDLINE, EMBASE, Cochrane library to October 2017, supplemented by manually retrieving ASCO, ESMO conference abstracts. The pooled hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS), and pooled odds ratios (OR) for the overall response rate (ORR) were calculated by Review Manager 5.3. RESULTS: The results indicated that the addition of anti-EGFR mAbs to FOLFOX regimen in RAS wild-type mCRC patients for the first-line treatment resulted in considerable improvements in PFS (HR = 0.70; 95% confidence interval [CI]: 0.59-0.82; P < .0001), OS (HR = 0.79; 95%CI: 0.67-0.92; P = .003), and ORR (OR = 2.56; 95% CI: 1.77-3.70; P < .00001) compared with chemotherapy alone. However, in RAS/BRAF wild patients, no significant differences were observed when anti-EGFR mAb was added to FLOX or XELOX regimen compared with chemotherapy alone with regard to OS and PFS, whereas FOLFOX+anti-EGFR mAb showed a marked superior OS and PFS (OS, HR = 0.77; 95% CI: 0.61-0.98; P = .03; PFS, HR = 0.68; 95% CI: 0.57-0.82; P < .00001). A meta-analysis including TAILOR and PRIME study suggests that primary tumor location (PTL) predicted a survival benefit when adding the EGFR antibody to FOLFOX regimen in RAS-wild mCRC patients (OS, HR for left-sided: 0.71; 95% CI: 0.59-0.85; P = .0002 and HR for right-sided: 0.90; 95% CI: 0.65-1.25; P = .53). However, the HR for PFS and ORR still suggests a benefit from the addition of anti-EGFR mAb in right-sided mCRC patients. CONCLUSION: So these results suggest anti-EGFR mAb and oxaliplatin are good partners in the FOLFOX regimen. The addition of EGFR antibody to FOLFOX markedly improved efficacy in RAS-wild patients with left-sided mCRC. In RAS/BRAF-wild patients, the efficacy is similar. For patients with right-sided tumor, a benefit showing a trendency in favor of anti-EGFR mAb can still seen. The molecular characteristics behind the tumor location need to be more explored urgently.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Capecitabina , Cetuximab/administración & dosificación , Neoplasias Colorrectales/genética , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Mutación , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Oxaloacetatos , Panitumumab , Modelos de Riesgos Proporcionales , Proteínas Proto-Oncogénicas B-raf/efectos de los fármacos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/genética , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento

RESUMEN

Activating KRAS mutations frequently occur in pancreatic, colorectal, and lung adenocarcinomas. While many attempts have been made to target oncogenic KRAS, no clinically useful therapies currently exist. Most efforts to target KRAS have focused on inhibiting the mutant protein; a less explored approach involves targeting KRAS at the transcriptional level. The promoter element of the KRAS gene contains a GC-rich nuclease hypersensitive site with three potential DNA secondary structure-forming regions. These are referred to as the Near-, Mid-, and Far-regions, on the basis of their proximity to the transcription start site. As a result of transcription-induced negative superhelicity, these regions can open up to form unique DNA secondary structures: G-quadruplexes on the G-rich strand and i-motifs on the C-rich strand. While the G-quadruplexes have been well characterized, the i-motifs have not been investigated as thoroughly. Here we show that the i-motif that forms in the C-rich Mid-region is the most stable and exists in a dynamic equilibrium with a hybrid i-motif/hairpin species and an unfolded hairpin species. The transcription factor heterogeneous nuclear ribonucleoprotein K (hnRNP K) was found to bind selectively to the i-motif species and to positively modulate KRAS transcription. Additionally, we identified a benzophenanthridine alkaloid that dissipates the hairpin species and destabilizes the interaction of hnRNP K with the Mid-region i-motif. This same compound stabilizes the three existing KRAS G-quadruplexes. The combined effect of the compound on the Mid-region i-motif and the G-quadruplexes leads to downregulation of KRAS gene expression. This dual i-motif/G-quadruplex-interactive compound presents a new mechanism to modulate gene expression.

Asunto(s)

G-Cuádruplex , Oligonucleótidos/farmacología , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Secuencia de Aminoácidos , Química Farmacéutica , Dicroismo Circular , Silenciador del Gen/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Mutación , Estructura Secundaria de Proteína , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/genética , Transcripción Genética/efectos de los fármacos

RESUMEN

Targeted therapies for cancers are sometimes only effective in a subset of patients with a particular biomarker status. In clinical development, the biomarker status is typically determined by an investigational-use-only/laboratory-developed test. A market ready test (MRT) is developed later to meet regulatory requirements and for future commercial use. In the USA, the clinical validation of MRT showing efficacy and safety profile of the targeted therapy in the biomarker subgroups determined by MRT is needed for pre-market approval. One of the major challenges in carrying out clinical validation is that the biomarker status per MRT is often missing for many subjects. In this paper, we treat biomarker status as a missing covariate and develop a novel pattern mixture model in the setting of a proportional hazards model for the time-to-event outcome variable. We specify a multinomial regression model for the missing biomarker statuses, and develop an expectation-maximization algorithm by the Method of Weights (Ibrahim, Journal of the American Statistical Association, 1990) to estimate the parameters in the regression model. We use Louis' formula (Louis, Journal of the Royal Statistical Society. Series B, 1982) to obtain standard errors estimates. We examine the performance of our method in extensive simulation studies and apply our method to a clinical trial in metastatic colorectal cancer. Copyright © 2017 John Wiley & Sons, Ltd.

Asunto(s)

Biomarcadores , Biometría/métodos , Modelos de Riesgos Proporcionales , Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos Fase III como Asunto , Neoplasias Colorrectales/tratamiento farmacológico , Simulación por Computador , Humanos , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de Regresión

RESUMEN

Opinion statement: The addition of targeted therapy to a 5-FU chemotherapy backbone is now a standard of care in metastatic colorectal cancer. Epidermal growth factor receptor (EGFR) inhibitors have been demonstrated to improve progression-free survival (PFS) and overall survival (OS) in the first line for patients with tumors that do not harbor KRAS exon 2 mutations. Eligibility criteria for most clinical trials involving EGFR inhibitors in recent years have used the absence of KRAS exon 2 mutation as the sole criteria for entry, as this specific mutation has been consistently shown to be predictive of a poor response to EGFR inhibitors. However, expanded analyses of first-line metastatic trials reveal that other RAS mutations, such as other KRAS mutations in exons 3 and 4, along with NRAS mutations, are predictive of poor responses to EGFR inhibitors as well. Testing for a full panel of these RAS mutations should be done prior to initiating treatment with an EGFR inhibitor. Further clinical trials are required to determine the predictive impact of each of these individual mutations. To date, they have been analyzed in the aggregate. The addition of targeted therapy, bevacizumab or an EGFR inhibitor, to a chemotherapy backbone should be considered for all appropriate patients. The relevant clinical trials that evaluated patients without any RAS mutation and compared an EGFR inhibitor to chemotherapy alone show a distinct advantage in overall survival and progression-free survival to the groups that received EGFR inhibition. The largest trial that compared bevacizumab with an EGFR inhibitor in the first line, CALGB/SWOG 80405, did not show a statistically significant difference between the two groups, making the use of bevacizumab, cetuximab, or panitumumab reasonable in the first line.

Asunto(s)

Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos/administración & dosificación , Bevacizumab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , Mutación/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Receptores ErbB/antagonistas & inhibidores , Exones , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento

RESUMEN

Rodent lung tumors are morphologically similar to a subtype of human lung adenocarcinomas. The objective of this study was to evaluate Kirsten rat sarcoma oncogene homolog (Kras), epidermal growth factor receptor (Egfr), and tumor protein 53 (Tp53) mutations, which are relevant to human lung cancer, in cobalt metal dust (CMD)-induced alveolar/bronchiolar tumors of B6C3F1/N mice and F344/NTac rats. Kras mutations were detected in 67% (mice) and 31% (rats) of CMD-induced lung tumors and were predominantly exon 1 codon 12 G to T transversions (80% in mice and 57% in rats). Egfr mutations were detected in 17% (both mice and rats) of CMD-induced lung tumors and were predominantly in exon 20 with 50% G to A transitions (mice and rats). Tp53 mutations were detected in 19% (mice) and 23% (rats) of CMD-induced lung tumors and were predominant in exon 5 (mice, 69% transversions) and exon 6 (rats, all transitions). No mutations were observed for these genes in spontaneous lung tumors or normal lungs from untreated controls. Ames assay indicated that CMD is mutagenic in the absence but not in the presence of S9 mix. Thus, the mutation data (G to T transversions) and Ames assay results suggest that oxidative damage to DNA may be a contributing factor in CMD-induced pulmonary carcinogenesis in rodents.

Asunto(s)

Adenocarcinoma Bronquioloalveolar/inducido químicamente , Adenocarcinoma Bronquioloalveolar/genética , Cobalto/toxicidad , Receptores ErbB/genética , Genes p53/genética , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Adenocarcinoma Bronquioloalveolar/patología , Animales , Análisis Mutacional de ADN , ADN de Neoplasias/biosíntesis , ADN de Neoplasias/genética , Polvo , Receptores ErbB/efectos de los fármacos , Exones/genética , Femenino , Genes p53/efectos de los fármacos , Exposición por Inhalación , Neoplasias Pulmonares/patología , Masculino , Ratones , Pruebas de Mutagenicidad , Mutación/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Ratas

RESUMEN

The hedgehog (Hh) pathway is aberrantly activated in a number of tumors. In medulloblastoma, basal cell carcinoma, and rhabdomyosarcoma, mutations in Hh pathway genes lead to ligand-independent pathway activation. In many other tumor types, ligand-dependent activation of Hh signaling is potentiated through crosstalk with other critical molecular signaling pathways. Among such pathways, RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, EGFR, and Notch are of particular interest because agents that selectively inhibit these pathways are available and can be readily combined with agents such as vismodegib, sonidegib (LDE225), and BMS-833923, which target smoothened-a key Hh pathway regulator. Numerous preclinical studies have revealed the ways in which Hh intersects with each of these pathways, and combination therapies have resulted in improved antitumor efficacy and survival in animal models. Hh also plays an important role in hematopoiesis and in the maintenance of BCR-ABL-driven leukemic stem cells. Thus, combined inhibition of the Hh pathway and BCR-ABL has emerged as a promising potential therapeutic strategy in chronic myeloid leukemia (CML). A number of clinical trials evaluating combinations of Hh inhibitors with other targeted agents are now underway in CML and a variety of solid tumors. This review highlights these trials and summarizes preclinical evidence of crosstalk between Hh and four other actionable pathways-RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, EGFR, and Notch-as well as the role of Hh in the maintenance of BCR-ABL-driven leukemic stem cells.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proteínas Hedgehog/metabolismo , Terapia Molecular Dirigida/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Receptor Cross-Talk/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Receptores ErbB/efectos de los fármacos , Receptores ErbB/metabolismo , Proteínas de Fusión bcr-abl/efectos de los fármacos , Proteínas de Fusión bcr-abl/metabolismo , Proteínas Hedgehog/efectos de los fármacos , Humanos , Janus Quinasa 2/antagonistas & inhibidores , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Receptores Notch/efectos de los fármacos , Receptores Notch/metabolismo , Serina-Treonina Quinasas TOR/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Quinasas raf/efectos de los fármacos , Quinasas raf/metabolismo

RESUMEN

BACKGROUND: The purpose of this study was to identify mechanisms of innate resistance to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib, in a panel of head and neck squamous cell carcinoma (HNSCC) cell lines. Specifically, we analyzed the role of HRAS mutations in erlotinib resistance. METHODS: Erlotinib sensitivity was determined by methyl thiazolyl-tetrazolium (MTT) assays. Molecular signaling pathways and somatic mutations were examined. Changes in sensitivity after modulation of HRAS expression were evaluated. RESULTS: All 7 cell lines were wild-type for EGFR and KRAS regardless of erlotinib sensitivity; however, 1 erlotinib-resistant cell line (HN31) harbored an HRAS G12D mutation. Downregulation of HRAS expression by small interfering RNA (siRNA) or short hairpin RNA (shRNA) in HN31 led to increased erlotinib sensitivity in vitro and in vivo. Transfection of activating HRAS-mutant (G12D and G12V) constructs into erlotinib-sensitive cell lines made them more resistant to erlotinib. CONCLUSION: Activating HRAS mutations can confer erlotinib resistance in an HRAS mutant HNSCC cell line.

Asunto(s)

Resistencia a Antineoplásicos/genética , Terapia Molecular Dirigida/métodos , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Quinazolinas/farmacología , Animales , Western Blotting , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/genética , Clorhidrato de Erlotinib , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/genética , Humanos , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Sensibilidad y Especificidad , Transducción de Señal/efectos de los fármacos , Carcinoma de Células Escamosas de Cabeza y Cuello , Transfección