KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.

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.

Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas.

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.

Variacion genetica del sistema renina-angiotensina y deporte de resistencia: relacion con el rendimiento y la prevencion de patologias / Genetic variation in the renin angiotensin system and endurance performance. Its relationship with performance and prevention of pathology

Algunos estudios recientes relacionan factores genéticos con patologías asociadas al ejercicio físico. El desarrollo de la enfermedad coronaria (infarto) y la hipertrofia ventricular han sido asociadas a la variación (polimorfismos) en el gen de la Enzima Convertidora de la Angiotensina (ECA). Los individuos homocigotos DD para el polimorfismo I/D de la ECA muestran un incremento significativo de la masa ventricular izquierda en respuesta al entrenamiento, comparados con sujetos con los genotipos II e ID. Los individuos II e ID, que, tienen unos niveles mas bajos de ECA en plasma, tendrían una mayor respuesta anabólica al ejercicio. En este sentido, se ha descrito un aumento de la frecuencia del alelo I entre remeros y alpinistas de elite. Considerando los antecedentes descritos, el objetivo de este trabajo es comparar la distribución de los genotipos dé los polimorfismos de los componentes del sistema renina angiotensina en sujetos sanos y en deportistas de alto nivel, analizando también la relación entre el genotipo y los niveles sanguíneos del enzima. Amplificando el ADN mediante la reacción en cadena de la polimerasa (PCR), determinamos el genotipo de cuarenta y cinco deportistas de élite (25 ciclistas y 20 corredores de fondo) y 400 controles sanos para el polimorfismo del gen de la ECA. El alelo I de la ECA presentaba una frecuencia significativamente mayor (p=0,0029) en los deportistas que en los controles sanos. Los niveles plasmáticos de ECA mostraron una fuerte correlación con el genotipo I/D en nuestra población. En conclusión, por su relación con el desarrollo de patologias cardíacas y con el rendimiento fisico, él polimorfismo de la ECA es un factor genético de interés para el deporte de alto rendimiento. El análisis de este marcador genético podría ser útil en la mejora del rendimiento físico y en la prevención de las patologías asociadas a la práctica deportiva (AU)