A pesar de su incidencia declinante a partir de la segunda mitad del siglo XX, el cáncer gástrico sigue representando la segunda causa de muerte por cáncer, tras la ocasionada por el de pulmón 1 . Los factores pronósticos para este tumor se pueden clasificar en dos grandes grupos: los factores pronósticos convencionales y los biológicos. Dentro de los factores del primer grupo están los que dependen del paciente y del tumor, así como los relacionados con el tipo de tratamiento. Con respecto a este último tipo de factor, y considerando que el tratamiento más efectivo para este tipo de tumor es el quirúrgico, resulta absolutamente clave para lograr una resecabilidad completa del tumor (R0, de acuerdo a la UICC: no tumor residual macroscópico, ni microscó-pico tras la cirugía). Sin embargo, como se puede apreciar en la Figura 1, aun en los casos quirúrgicamente resecables, la probabilidad de supervivencia a los cinco años apenas supera el 40%. Es más, la probabilidad de supervivencia libre de enfermedad es muy similar a la de supervivencia global, lo que da una idea de la agresividad biológica de estos tumores. Por ello, resulta importante en la práctica clínica, la consideración de factores pronósticos que nos permitan una evaluación más óptima de la agresividad de los carcinomas gástricos resecables quirúrgicamente, y que también posibiliten el establecimiento de nuevas dianas terapéuticas. Factores pronósticos clásicosEntre los factores pronósticos convencionales que han sido evaluados en el cáncer gástrico, se encuentran la edad y sexo de los pacientes, la localización tumoral, configuración macroscópica del tumor, estadio tumoral, tipo y grado histológico. El estadio tumoral, de acuerdo con la clasificación TNM, que es la más empleada en occidente, es el factor pronóstico más importante en los carcinomas gástricos resecables. La localización tumoral en cardias y en muñón gástrico de pacientes que fueron sometidos a gastrectomía parcial por enfermedad ulcerosa, también está asociada con un peor pronóstico. En general, la mayoría de los estudios indican que la configuración macroscópica del crecimiento de tipo linitis plástica (clasificación de Borrmann), el grado histológico indiferenciado, el tipo histológico difuso (criterios de Lauren), así como aspectos histopatológicos tales como la invasión vascular, perineural o linfática, se asocian con un peor pronóstico del cáncer gástrico resecable. De todos esos factores, en un estudio realizado sobre 151 pacientes con cáncer gástrico resecable que fueron sometidas a un período medio de seguimiento clínico de 36,6 meses (mediana: 24 meses) en los Hospitales Central de Asturias, de Oviedo y de Jove, de Gijón, tan sólo el estadio tumoral (p=0,00001), la localización tumoral (p=0,005) y el tipo histológico de los tumores (p=0,004) estuvieron significativamente asociados con la supervivencia de los pacientes.43

Dysregulation of ERK signaling is a common event in malignancy. Receptor activation of RAS leads to dimerization and activation of RAF kinase, which in turn activates ERK. Physiologic activation of the pathway is limited by ERK dependent feedback inhibition of RAS activation and other components of the pathway. Oncogenic mutations and translocations of RAF family members have been identified in many human tumors and serve as drivers of tumor growth. We now show that these mutants are active despite feedback inhibition of RAS and that this is associated with dysregulated ERK output. All translocations and almost all of the RAF mutants tested so far form RAS-independent constitutive dimers, the activity of which is dependent on their dimerization. Mutations at one site, V600E and V600K allow RAF to function as a monomer in cells with low RAS activity and as a RAS-dependent dimer in cells with adequate RAS activity. In tumors expressing any of these mutants, RAF/MEK/ERK activity is elevated despite feedback inhibition of RAS. Currently available RAF inhibitors bind to one protomer of the RAF dimer and cause negative cooperativity of binding to the second site. This is sometimes associated with transactivation of the unbound protomer. These inhibitors cannot be used to inhibit ERK signaling in tumors in which ERK is driven by RAF-dimers (those with mutant RAS, NF1 loss, atypical RAF mutations, RAF translocations.) In contrast, in tumors with V600E BRAF mutations, ERK causes strong feedback inhibition of RAS and V600E BRAF exists as a monomer that is inhibited by these drugs. Acquired resistance to RAF inhibitors usually results from a molecular lesion that causes RAS-dependent or independent dimerization of V600E (NRAS mutation, V600E BRAF amplification, V600E aberrantly spliced isoform.) Current RAF inhibitors inhibit V600E BRAF dimers at concentrations 10-100 fold greater than those required to inhibit the corresponding monomer in cells. We take this as a provisional measure of the degree of negative cooperativity of binding to the second site. We have now identified inhibitors that inhibit V600E dimers at concentrations close (1-3 fold higher) than those required to inhibit the monomer. They do not cause dissociation of dimers and their inhibition is abolished by gatekeeper mutations. Phenotypically, therefore, binding of these compounds to dimers is associated with only minimal negative cooperativity. These drugs inhibit ERK signaling and the proliferation of tumor cells with atypical BRAF mutations and translocations as well as V600E melanoma models with acquired resistance to Vemurafenib. However, they are much less active in cancer cells with KRAS mutation or receptor-dependent activation of RAF. Selective inhibitors of subsets of RAF dimers may allow effective ERK inhibition of large subset of tumors without inhibiting signaling in normal cells. Citation Format: Zhan Yao, Merna Torres, Min Wei, Aphrothiti Hanrahan, Omar Abdel-Wahab, David Solit, Lusong Luo, Poulikos Poulikakos, Neal Rosen. Oncogenic RAF mutants that signal as functional dimers are resistant to current RAF inhibitors but sensitive to a novel inhibitor of RAF dimer kinase activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3706. doi:10.1158/1538-7445.AM2014-3706

Activating BRAF mutants drive human tumors by dysregulating ERK signaling despite ERK-dependent feedback suppression of RAS. These RAF mutants become RAS independent, by either of two mechanisms, and they are thus unaffected by feedback inhibition of upstream signaling. Recently, it has become clear that mutation activation of MEK1 or MEK2 occur at appreciable frequency in human tumors, but the mechanism of activation of these mutants and whether they remain dependent on upstream activation of RAS or RAF signaling remains unknown. Here we characterized the mechanism of activation of 18 recurrent MEK1 mutants identified in human cancer. Based on these data, they fall into three classes. The kinase activity of first class remains dependent on RAF mediated phosphorylation of S218 and S222; the second class of MEK mutants has basal RAF-independent activity, but can be further stimulated by RAF and the third class no longer requires phosphorylation of S218 and S222 and signals in a RAF independent manner. These features determined their sensitivity to ERK-dependent feedback regulation and the ability to drive ERK signaling output in cells. The more RAF-independent activity the mutants acquired, the better they could activate downstream ERK pathway, leading to increased transforming activities in MEF cells in the absence of RAF. This is consistent with their genetic association with RAS, RAF and NF1 mutations in human tumors. The Class 3 RAF-independent MEK1 mutants tend to be mutually exclusive with those mutants, while coexistence with RAS/RAF/NF1 mutations is frequently observed in tumors with Class 1 or 2 MEK1 mutants. Moreover, functional class correlated with sensitivities of ERK signaling driven by these mutants to MEK inhibitors that function by different mechanisms. Unlike RAF dependent or regulated MEK1 mutants, the ERK signaling driven by RAF independent MEK1 mutants is insensitive to an allosteric MEK inhibitor that functions by preventing RAF mediated MEK phosphorylation. However, signaling driven by all classes of MEK1 mutants is sensitive to an ATP competitive MEK1 inhibitor which targets MEK1 kinase activity. Citation Format: Yijun Gao, Matthew T. Chang, Daniel McKay, Rona D. Yaeger, Merna Torres, Keven Muniz, Drosten Matthias, Omar I. Abdel-Wahab, Mariano Barbacid, Giordano Caponigro, Darrin Stuart, David Solit, Barry S. Taylor, Zhan Yao, Neal Rosen. Activation mechanisms of cancer associated MEK1 mutants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 395. doi:10.1158/1538-7445.AM2017-395