RESUMEN
KRASG12D is the most frequent KRAS mutation in human cancer. In this issue, Zhou et al. describe a novel KRASG12D inhibitor, HRS-4642, that shows potent and selective anti-tumor activity across various models and synergizes with proteasome inhibitors. Responses have also been observed in patients during an ongoing phase 1 trial.
Asunto(s)
Proteínas Proto-Oncogénicas p21(ras) , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias/genética , Mutación , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Animales , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéuticoRESUMEN
Approved BRAF inhibitors have shown limited clinical benefit due to recurrent disease progression. In a recent Cancer Discovery paper, Yaeger et al. show that a next-generation BRAF inhibitor, PF-07799933, has widespread therapeutic activity in experimental models and patients who were refractory to treatment with approved BRAF inhibitors.
Asunto(s)
Resistencia a Antineoplásicos , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas B-raf , Humanos , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/genética , Melanoma/inmunología , MutaciónRESUMEN
Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.
Asunto(s)
Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Reposicionamiento de Medicamentos , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Combinación de Medicamentos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Mutación , Línea Celular TumoralRESUMEN
KRASG12C inhibitors have revolutionized the clinical management of patients with KRASG12C-mutant lung adenocarcinoma. However, patient exposure to these inhibitors leads to the rapid onset of resistance. In this study, we have used genetically engineered mice to compare the therapeutic efficacy and the emergence of tumor resistance between genetic ablation of mutant Kras expression and pharmacological inhibition of oncogenic KRAS activity. Whereas Kras ablation induces massive tumor regression and prevents the appearance of resistant cells in vivo, treatment of KrasG12C/Trp53-driven lung adenocarcinomas with sotorasib, a selective KRASG12C inhibitor, caused a limited antitumor response similar to that observed in the clinic, including the rapid onset of resistance. Unlike in human tumors, we did not observe mutations in components of the RAS-signaling pathways. Instead, sotorasib-resistant tumors displayed amplification of the mutant Kras allele and activation of xenobiotic metabolism pathways, suggesting that reduction of the on-target activity of KRASG12C inhibitors is the main mechanism responsible for the onset of resistance. In sum, our results suggest that resistance to KRAS inhibitors could be prevented by achieving a more robust inhibition of KRAS signaling mimicking the results obtained upon Kras ablation.
Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Animales , Ratones , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/patología , Mutación , Oncogenes , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Transducción de SeñalRESUMEN
KRASG12D is the most frequent KRAS mutation in human cancer with particularly high frequencies in pancreatic and colorectal cancer. Informed by the structure of the KRASG12C inhibitor adagrasib, Hallin et al. have now, through multiple rounds of structure-based drug design, identified and validated a potent, selective, and noncovalent KRASG12D inhibitor, MRTX1133. This study demonstrated that MRTX1133 inhibited both the inactive and active state of KRASG12D and showed potent antitumor activity in several preclinical models of pancreatic and colorectal cancer, especially when combined with cetuximab, a monoclonal antibody against the EGFR, or BYL-719, a potent PI3Kα inhibitor.
Asunto(s)
Neoplasias Colorrectales , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Mutación/genética , Piperazinas , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patologíaRESUMEN
The kinase suppressor of rat sarcoma (RAS) proteins (KSR1 and KSR2) have long been considered as scaffolding proteins required for optimal mitogen-activated protein kinase (MAPK) pathway signalling. However, recent evidence suggests that they play a more complex role within this pathway. Here, we demonstrate that ectopic expression of KSR1 or KSR2 is sufficient to activate the MAPK pathway and to induce cell proliferation in the absence of RAS proteins. In contrast, the ectopic expression of KSR proteins is not sufficient to induce cell proliferation in the absence of either rapidly accelerated fibrosarcoma (RAF) or MAPK-ERK kinase proteins, indicating that they act upstream of RAF. Indeed, KSR1 requires dimerization with at least one member of the RAF family to stimulate proliferation, an event that results in the translocation of the heterodimerized RAF protein to the cell membrane. Mutations in the conserved aspartic acid-phenylalanine-glycine motif of KSR1 that affect ATP binding impair the induction of cell proliferation. We also show that increased expression levels of KSR1 decrease the responsiveness to the KRASG12C inhibitor sotorasib in human cancer cell lines, thus suggesting that increased levels of expression of KSR may make tumour cells less dependent on KRAS oncogenic signalling.
Asunto(s)
Proteínas Quinasas Activadas por Mitógenos , Proteínas Quinasas/metabolismo , Proteínas Proto-Oncogénicas p21(ras) , Genes ras , Humanos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Transducción de SeñalRESUMEN
For decades, KRAS mutant lung adenocarcinomas (LUAD) have been refractory to therapeutic strategies based on personalized medicine owing to the complexity of designing inhibitors to selectively target KRAS and downstream targets with acceptable toxicities. The recent development of selective KRASG12C inhibitors represents a landmark after 40 years of intense research efforts since the identification of KRAS as a human oncogene. Here, we discuss the mechanisms responsible for the rapid development of resistance to these inhibitors, as well as potential strategies to overcome this limitation. Other therapeutic strategies aimed at inhibiting KRAS oncogenic signaling by targeting either upstream activators or downstream effectors are also reviewed. Finally, we discuss the effect of targeting the mitogen-activated protein kinase (MAPK) pathway, both based on the failure of MEK and ERK inhibitors in clinical trials, as well as on the recent identification of RAF1 as a potential target due to its MAPK-independent activity. These new developments, taken together, are likely to open new avenues to effectively treat KRAS mutant LUAD.
Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación/genética , Oncogenes , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
In mammals, the KRAS locus encodes two protein isoforms, KRAS4A and KRAS4B, which differ only in their C terminus via alternative splicing of distinct fourth exons. Previous studies have shown that whereas KRAS expression is essential for mouse development, the KRAS4A isoform is expendable. Here, we have generated a mouse strain that carries a terminator codon in exon 4B that leads to the expression of an unstable KRAS4B154 truncated polypeptide, hence resulting in a bona fide Kras4B-null allele. In contrast, this terminator codon leaves expression of the KRAS4A isoform unaffected. Mice selectively lacking KRAS4B expression developed to term but died perinatally because of hypertrabeculation of the ventricular wall, a defect reminiscent of that observed in embryos lacking the Kras locus. Mouse embryonic fibroblasts (MEFs) obtained from Kras4B-/- embryos proliferated less than did wild-type MEFs, because of limited expression of KRAS4A, a defect that can be compensated for by ectopic expression of this isoform. Introduction of the same terminator codon into a KrasFSFG12V allele allowed expression of an endogenous KRAS4AG12V oncogenic isoform in the absence of KRAS4B. Exposure of Kras+/FSF4AG12V4B- mice to Adeno-FLPo particles induced lung tumors with complete penetrance, albeit with increased latencies as compared with control Kras+/FSFG12V animals. Moreover, a significant percentage of these mice developed proximal metastasis, a feature seldom observed in mice expressing both mutant isoforms. These results illustrate that expression of the KRAS4AG12V mutant isoform is sufficient to induce lung tumors, thus suggesting that selective targeting of the KRAS4BG12V oncoprotein may not have significant therapeutic consequences.
Asunto(s)
Adenocarcinoma del Pulmón/secundario , Neoplasias Pulmonares/patología , Proteínas Proto-Oncogénicas p21(ras)/fisiología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Animales , Apoptosis , Proliferación Celular , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Isoformas de Proteínas , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
RAS proteins are key players in multiple cellular processes. To study the role of RAS proteins individually or in combination, we have developed MEFs that can be rendered RASless, i.e., devoid of all endogenous RAS isoforms. These cells have significantly contributed to our understanding of the requirements for RAS functions in cell proliferation as well as their implications in diverse cellular processes. Here, we describe methods using RASless MEFs to study RAS-dependent cellular activities with special emphasis on proliferation. We provide the details to identify inducers of RAS-independent proliferation in colony assays. We recommend following these stringent guidelines to avoid false-positive results. Moreover, this protocol can be adapted to generate RASless MEFs ectopically expressing RAS variants to interrogate their function in the absence of endogenous RAS isoforms or to perform experiments in the absence of RAS. Finally, we also describe protocols to generate and use RASless MEFs for cell cycle analyses using the FUCCI cell cycle indicator.
Asunto(s)
Ciclo Celular , Proliferación Celular , Embrión de Mamíferos/metabolismo , Fibroblastos/metabolismo , Mutación , Proteínas ras/administración & dosificación , Proteínas ras/metabolismo , Animales , Células Cultivadas , Embrión de Mamíferos/citología , Fibroblastos/citología , Ratones , Ratones Noqueados , Proteínas ras/genéticaAsunto(s)
Neoplasias Pulmonares/genética , Mutación/genética , Proteínas Proto-Oncogénicas c-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína p53 Supresora de Tumor/genética , Animales , Línea Celular Tumoral , Progresión de la Enfermedad , Humanos , Neoplasias Pulmonares/patología , Fosforilación/genética , Proteínas Proto-Oncogénicas/genéticaRESUMEN
KRAS mutant lung adenocarcinomas remain intractable for targeted therapies. Genetic interrogation of KRAS downstream effectors, including the MAPK pathway and the interphase CDKs, identified CDK4 and RAF1 as the only targets whose genetic inactivation induces therapeutic responses without causing unacceptable toxicities. Concomitant CDK4 inactivation and RAF1 ablation prevented tumor progression and induced complete regression in 25% of KRAS/p53-driven advanced lung tumors, yet a significant percentage of those tumors that underwent partial regression retained a population of CDK4/RAF1-resistant cells. Characterization of these cells revealed two independent resistance mechanisms implicating hypermethylation of several tumor suppressors and increased PI3K activity. Importantly, these CDK4/RAF1-resistant cells can be pharmacologically controlled. These studies open the door to new therapeutic strategies to treat KRAS mutant lung cancer, including resistant tumors.
Asunto(s)
Adenocarcinoma del Pulmón/genética , Quinasa 4 Dependiente de la Ciclina/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas c-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína p53 Supresora de Tumor/metabolismo , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/patología , Animales , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Quinasa 4 Dependiente de la Ciclina/metabolismo , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Silenciador del Gen , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos C57BL , Mutación , Proteínas Proto-Oncogénicas c-raf/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
KRAS mutations occur in a quarter of all of human cancers, yet no selective drug has been approved to treat these tumors. Despite the recent development of drugs that block KRASG12C, the majority of KRAS oncoproteins remain undruggable. Here, we review recent efforts to validate individual components of the mitogen-activated protein kinase (MAPK) pathway as targets to treat KRAS-mutant cancers by comparing genetic information derived from experimental mouse models of KRAS-driven lung and pancreatic tumors with the outcome of selective MAPK inhibitors in clinical trials. We also review the potential of RAF1 as a key target to block KRAS-mutant cancers.
Asunto(s)
Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Terapia Molecular Dirigida , Mutación , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genética , Humanos , Neoplasias/genética , Neoplasias/patologíaRESUMEN
Malignant transformation entails important changes in the control of cell proliferation through the rewiring of selected signaling pathways. Cancer cells then become very dependent on the proper function of those pathways, and their inhibition offers therapeutic opportunities. Here we identify the stress kinase p38α as a nononcogenic signaling molecule that enables the progression of KrasG12V-driven lung cancer. We demonstrate in vivo that, despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α contributes to the proliferation and malignization of lung cancer epithelial cells. We show that high expression levels of p38α correlate with poor survival in lung adenocarcinoma patients, and that genetic or chemical inhibition of p38α halts tumor growth in lung cancer mouse models. Moreover, we reveal a lung cancer epithelial cell-autonomous function for p38α promoting the expression of TIMP-1, which in turn stimulates cell proliferation in an autocrine manner. Altogether, our results suggest that epithelial p38α promotes KrasG12V-driven lung cancer progression via maintenance of cellular self-growth stimulatory signals.
Asunto(s)
Adenocarcinoma del Pulmón/enzimología , Neoplasias Pulmonares/enzimología , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/patología , Animales , Línea Celular Tumoral , Proliferación Celular , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Pulmón/enzimología , Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa 14 Activada por Mitógenos/genética , Procesos Neoplásicos , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
Five-year survival for pancreatic ductal adenocarcinoma (PDAC) patients remains below 7% due to the lack of effective treatments. Here, we report that combined ablation of EGFR and c-RAF expression results in complete regression of a significant percentage of PDAC tumors driven by Kras/Trp53 mutations in genetically engineered mice. Moreover, systemic elimination of these targets induces toxicities that are well tolerated. Response to this targeted therapy correlates with transcriptional profiles that resemble those observed in human PDACs. Finally, inhibition of EGFR and c-RAF expression effectively blocked tumor progression in nine independent patient-derived xenografts carrying KRAS and TP53 mutations. These results open the door to the development of targeted therapies for PDAC patients.
Asunto(s)
Carcinoma Ductal Pancreático/tratamiento farmacológico , Receptores ErbB/metabolismo , Clorhidrato de Erlotinib/farmacología , Gefitinib/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-raf/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Carcinoma Ductal Pancreático/enzimología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación , Neoplasias Pancreáticas/enzimología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas c-raf/genética , Proteínas Proto-Oncogénicas c-raf/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Transducción de Señal , Carga Tumoral/efectos de los fármacos , Proteína p53 Supresora de Tumor/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
MEK inhibition in combination with a glycogen synthase kinase-3ß (GSK3ß) inhibitor, referred as the 2i condition, favors pluripotency in embryonic stem cells (ESCs). However, the mechanisms by which the 2i condition limits ESC differentiation and whether RAS proteins are involved in this phenomenon remain poorly understood. Here we show that RAS nullyzygosity reduces the growth of mouse ESCs (mESCs) and prohibits their differentiation. Upon RAS deficiency or MEK inhibition, ERF (E twenty-six 2 [Ets2]-repressive factor), a transcriptional repressor from the ETS domain family, translocates to the nucleus, where it binds to the enhancers of pluripotency factors and key RAS targets. Remarkably, deletion of Erf rescues the proliferative defects of RAS-devoid mESCs and restores their capacity to differentiate. Furthermore, we show that Erf loss enables the development of RAS nullyzygous teratomas. In summary, this work reveals an essential role for RAS proteins in pluripotency and identifies ERF as a key mediator of the response to RAS/MEK/ERK inhibition in mESCs.
Asunto(s)
Células Madre Embrionarias/citología , Genes ras , Proteínas Represoras/fisiología , Animales , Diferenciación Celular , Línea Celular , Células Madre Embrionarias/metabolismo , Elementos de Facilitación Genéticos , Eliminación de Gen , Ratones , Ratones Desnudos , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Teratoma/genéticaRESUMEN
The transcriptional repressor Capicua (CIC) has emerged as an important rheostat of cell growth regulated by RAS/MAPK signaling. Cic was originally discovered in Drosophila, where it was shown to be inactivated by MAPK signaling downstream of the RTKs Torso and EGFR, which results in signal-dependent responses that are required for normal cell fate specification, proliferation and survival of developing and adult tissues. CIC is highly conserved in mammals, where it is also negatively regulated by MAPK signaling. Here, we review the roles of CIC during mammalian development, tissue homeostasis, tumor formation and therapy resistance. Available data indicate that CIC is involved in multiple biological processes, including lung development, liver homeostasis, autoimmunity and neurobehavioral processes. Moreover, CIC has been shown to be involved in tumor development as a tumor suppressor, both in human as well as in mouse models. Finally, several lines of evidence implicate CIC as a determinant of sensitivity to EGFR and MAPK pathway inhibitors, suggesting that CIC may play a broader role in human cancer than originally anticipated.
Asunto(s)
Proteínas Represoras/metabolismo , Transducción de Señal , Proteínas ras/metabolismo , Animales , Drosophila/crecimiento & desarrollo , Drosophila/metabolismo , Resistencia a Antineoplásicos/genética , Regulación del Desarrollo de la Expresión Génica , Humanos , Neoplasias/genética , Neoplasias/patología , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Represoras/genéticaRESUMEN
Mutations at multiple sites in MEK1 occur in cancer, suggesting that their mechanisms of activation might be different. We analyzed 17 tumor-associated MEK1 mutants and found that they drove ERK signaling autonomously or in a RAS/RAF-dependent manner. The latter are sensitive to feedback inhibition of RAF, which limits their functional output, and often cooccur with RAS or RAF mutations. They act as amplifiers of RAF signaling. In contrast, another class of mutants deletes a hitherto unrecognized negative regulatory segment of MEK1, is RAF- and phosphorylation-independent, is unaffected by feedback inhibition of upstream signaling, and drives high ERK output and transformation in the absence of RAF activity. Moreover, these RAF-independent mutants are insensitive to allosteric MEK inhibitors, which preferentially bind to the inactivated form of MEK1. All the mutants are sensitive to an ATP-competitive MEK inhibitor. Thus, our study comprises a novel therapeutic strategy for tumors driven by RAF-independent MEK1 mutants.Significance: Mutants with which MEK1 mutants coexist and their sensitivity to inhibitors are determined by allele-specific properties. This study shows the importance of functional characterization of mutant alleles in single oncogenes and identifies a new class of MEK1 mutants, insensitive to current MEK1 inhibitors but treatable with a new ATP-competitive inhibitor. Cancer Discov; 8(5); 648-61. ©2018 AACR.See related commentary by Maust et al., p. 534This article is highlighted in the In This Issue feature, p. 517.
Asunto(s)
Alelos , MAP Quinasa Quinasa 1/genética , Mutación , Adenosina Trifosfato/metabolismo , Animales , Línea Celular , Resistencia a Antineoplásicos/genética , Humanos , MAP Quinasa Quinasa 1/química , Ratones , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Fosforilación , Unión Proteica , Conformación Proteica , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-raf/metabolismo , Eliminación de Secuencia , Transducción de Señal/efectos de los fármacos , Quinasas raf/metabolismoRESUMEN
A quarter of all solid tumors harbor KRAS oncogenes. Yet, no selective drugs have been approved to treat these malignancies. Genetic interrogation of the MAPK pathway revealed that systemic ablation of MEK or ERK kinases in adult mice prevent tumor development but are unacceptably toxic. Here, we demonstrate that ablation of c-RAF expression in advanced tumors driven by KrasG12V/Trp53 mutations leads to significant tumor regression with no detectable appearance of resistance mechanisms. Tumor regression results from massive apoptosis. Importantly, systemic abrogation of c-RAF expression does not inhibit canonical MAPK signaling, hence, resulting in limited toxicities. These results are of significant relevance for the design of therapeutic strategies to treat K-RAS mutant cancers.
Asunto(s)
Adenocarcinoma del Pulmón/genética , Genes ras/genética , Mutación/genética , Proteínas Proto-Oncogénicas c-raf/metabolismo , Proteínas ras/genética , Animales , Línea Celular Tumoral , Ratones , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
K-RAS signaling has been intensely studied for over 40 years. Yet, as of today, no drugs have been approved to treat K-RAS mutant cancers. Since the turn of the century, scientists have used genetically engineered mouse (GEM) models to reproduce K-RAS mutant cancers in a laboratory setting to elucidate those molecular events responsible for the onset and progression of these tumors and to identify suitable therapies. In this review, we outline a brief description of available GEM models for two tumor types known to be driven by K-RAS mutations: lung adenocarcinoma and pancreatic ductal adenocarcinoma. In addition, we summarize a series of studies that have used these GEM tumor models to validate, either by genetic or pharmacological approaches, the therapeutic potential of a variety of targets, with the ultimate goal of translating these results to the clinical setting.
Asunto(s)
Adenocarcinoma del Pulmón , Carcinoma Ductal Pancreático , Modelos Animales de Enfermedad , Neoplasias Pulmonares , Neoplasias Pancreáticas , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/terapia , Animales , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/terapia , Genes ras , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Ratones , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Farmacogenética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2). Here we characterize a third class of BRAF mutants-those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS-GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling. The model suggests that dysregulation of signalling by these mutants in tumours requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbour RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signalling. These tumours are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. We have thus defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.