PI3K activation promotes resistance to eribulin in HER2-negative breast cancer.

BACKGROUND: Eribulin is a microtubule-targeting agent approved for the treatment of advanced or metastatic breast cancer (BC) previously treated with anthracycline- and taxane-based regimens. PIK3CA mutation is associated with worse response to chemotherapy in oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic BC. We aimed to evaluate the role of phosphoinositide 3-kinase (PI3K)/AKT pathway mutations in eribulin resistance. METHODS: Resistance to eribulin was evaluated in HER2- BC cell lines and patient-derived tumour xenografts, and correlated with a mutation in the PI3K/AKT pathway. RESULTS: Eleven out of 23 HER2- BC xenografts treated with eribulin exhibited disease progression. No correlation with ER status was detected. Among the resistant models, 64% carried mutations in PIK3CA, PIK3R1 or AKT1, but only 17% among the sensitive xenografts (P = 0.036). We observed that eribulin treatment induced AKT phosphorylation in vitro and in patient tumours. In agreement, the addition of PI3K inhibitors reversed primary and acquired resistance to eribulin in xenograft models, regardless of the genetic alterations in PI3K/AKT pathway or ER status. Mechanistically, PI3K blockade reduced p21 levels likely enabling apoptosis, thus sensitising to eribulin treatment. CONCLUSIONS: PI3K pathway activation induces primary resistance or early adaptation to eribulin, supporting the combination of PI3K inhibitors and eribulin for the treatment of HER2- BC patients.

Communication skills training in undergraduate nursing programs in Spain.

OBJECTIVES: of the present cross sectional study were to analyze the offer of subjects with communication skills in the nursing degree in Spain and to describe the distribution of these subjects. Documentary, systematic and independent search of web pages from Spanish universities was carried out to collect the following variables: subjects with communication skills, course in which the subject is taught, type of teaching (exclusive or combined), type of subject (compulsory or optional) and number of credits on communication skills. Although an average of 3.6 subjects per center was offered, most of the subjects were combined and with little communication content load. In one third of the centers, the offer was below 2.3 credits. Only 1 in 6 centers had exclusive communication skills subjects, and a quarter of them were optional. The teaching load of communication contents was highest in optional subjects. The offer of communication skills contents in Spanish Nursing Schools was scarce and very heterogeneous between centers and between courses in a center, with excessive presence of combined and optional subjects. Our results may be useful when developing the teaching guides for subjects with communication skills, as well as when defining communication competencies in the different Nursing Schools.

MEK plus PI3K/mTORC1/2 Therapeutic Efficacy Is Impacted by TP53 Mutation in Preclinical Models of Colorectal Cancer.

PURPOSE: PI3K pathway activation occurs in concomitance with RAS/BRAF mutations in colorectal cancer, limiting the sensitivity to targeted therapies. Several clinical studies are being conducted to test the tolerability and clinical activity of dual MEK and PI3K pathway blockade in solid tumors. EXPERIMENTAL DESIGN: In the present study, we explored the efficacy of dual pathway blockade in colorectal cancer preclinical models harboring concomitant activation of the ERK and PI3K pathways. Moreover, we investigated if TP53 mutation affects the response to this therapy. RESULTS: Dual MEK and mTORC1/2 blockade resulted in synergistic antiproliferative effects in cell lines bearing alterations in KRAS/BRAF and PIK3CA/PTEN. Although the on-treatment cell-cycle effects were not affected by the TP53 status, a marked proapoptotic response to therapy was observed exclusively in wild-type TP53 colorectal cancer models. We further interrogated two independent panels of KRAS/BRAF- and PIK3CA/PTEN-altered cell line- and patient-derived tumor xenografts for the antitumor response toward this combination of agents. A combination response that resulted in substantial antitumor activity was exclusively observed among the wild-type TP53 models (two out of five, 40%), but there was no such response across the eight mutant TP53 models (0%). Interestingly, within a cohort of 14 patients with colorectal cancer treated with these agents for their metastatic disease, two patients with long-lasting responses (32 weeks) had TP53 wild-type tumors. CONCLUSIONS: Our data support that, in wild-type TP53 colorectal cancer cells with ERK and PI3K pathway alterations, MEK blockade results in potent p21 induction, preventing apoptosis to occur. In turn, mTORC1/2 inhibition blocks MEK inhibitor-mediated p21 induction, unleashing apoptosis. Clin Cancer Res; 21(24); 5499-510. ©2015 AACR.

RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer.

The PI3K signaling pathway regulates diverse cellular processes, including proliferation, survival, and metabolism, and is aberrantly activated in human cancer. As such, numerous compounds targeting the PI3K pathway are currently being clinically evaluated for the treatment of cancer, and several have shown some early indications of efficacy in breast cancer. However, resistance against these agents, both de novo and acquired, may ultimately limit the efficacy of these compounds. Here, we have taken a systematic functional approach to uncovering potential mechanisms of resistance to PI3K inhibitors and have identified several genes whose expression promotes survival under conditions of PI3K/mammalian target of rapamycin (PI3K/mTOR) blockade, including the ribosomal S6 kinases RPS6KA2 (RSK3) and RPS6KA6 (RSK4). We demonstrate that overexpression of RSK3 or RSK4 supports proliferation upon PI3K inhibition both in vitro and in vivo, in part through the attenuation of the apoptotic response and upregulation of protein translation. Notably, the addition of MEK- or RSK-specific inhibitors can overcome these resistance phenotypes, both in breast cancer cell lines and patient-derived xenograft models with elevated levels of RSK activity. These observations provide a strong rationale for the combined use of RSK and PI3K pathway inhibitors to elicit favorable responses in breast cancer patients with activated RSK.

PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition.

UNLABELLED: PARP inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 3-kinase (PI3K) signaling pathway preserves HR steady state. We hypothesized that in BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors. We show in TNBC cells that PI3K inhibition leads to DNA damage, downregulation of BRCA1/2, gain in poly-ADP-ribosylation, and subsequent sensitization to PARP inhibition. In TNBC patient-derived primary tumor xenografts, dual PI3K and PARP inhibition with BKM120 and olaparib reduced the growth of tumors displaying BRCA1/2 downregulation following PI3K inhibition. PI3K-mediated BRCA downregulation was accompanied by extracellular signal-regulated kinase (ERK) phosphorylation. Overexpression of an active form of MEK1 resulted in ERK activation and downregulation of BRCA1, whereas the MEK inhibitor AZD6244 increased BRCA1/2 expression and reversed the effects of MEK1. We subsequently identified that the ETS1 transcription factor was involved in the ERK-dependent BRCA1/2 downregulation and that knockdown of ETS1 led to increased BRCA1/2 expression, limiting the sensitivity to combined BKM120 and olaparib in 3-dimensional culture. SIGNIFICANCE: Treatment options are limited for patients with TNBCs. PARP inhibitors have clinical activity restricted to a small subgroup of patients with BRCA mutations. Here, we show that PI3K blockade results in HR impairment and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine PI3K and PARP inhibitors in this indication. Our findings could greatly expand the number of patients with breast cancer that would benefit from therapy with PARP inhibitors. On the basis of our findings, a clinical trial with BKM120 and olaparib is being initiated in patients with TNBCs.

Análisis factorial de los criterios de criticidad de las tareas enunciadas en la Encuesta de Análisis de Puestos de la Administración General del País Vasco (AGPV) / Factor analysis of task criticality criteria in a Job Analysis Survey for the Basque General Administration

En el contexto del análisis de puestos realizado en la Administración General del País Vasco entre los años 2002 y 2004, 2.171 personas de todas las categorías profesionales (el 44,98% del total) contestaron una encuesta sobre su puesto de trabajo. Esta encuesta incluía un cuestionario sobre la relevancia o criticidad de las tareas que realizan, en el que cada persona que contestó, seleccionó y/o enunció las tareas que ejecutaba y las valoró en cuatro dimensiones: Frecuencia, Duración, Consecuencias y Dificultad, según una escala de 1 a 7.Se enunciaron un total de 36.636 tareas. Ante la hipótesis de que las cuatro dimensiones incluidas en el cuestionario estén relacionadas entre sí y con el objetivo de reducir el número de variables del cuestionario sin pérdida significativa de información, se someten las 36.636 tareas valoradas a un análisis factorial exploratorio por el método de análisis de los componentes principales y rotación varimax. El resultado es una estructura factorial de dos factores, denominados Complejidad y Frecuencia, que explican el 78,761% de la varianza y que permiten que el cuestionario sea más rápido de responder y más claro de interpretar. Se discuten las implicaciones futuras de los resultados obtenidos (AU)

From 2002 to 2004, a survey was conducted in the Basque General Administration among 2,171 employees across all job levels (44.98% of the total), as part of a job analysis which included a questionnaire about the relevance or criticality of tasks carried out. All workers surveyed chose and stated the tasks they performed rating them 1-7 according to the frequency, duration, implications and difficulty. The result yielded 36,636 tasks. Considering the likely mutual relationship of these four dimensions and with a view to reducing the number of variables without a loss of information, an exploratory factor analysis using principal components method and varimax rotation was carried out. It revealed a two-factor factorial solution accounting for 78.761% of the variance. These two factors are complexity and frequency and will enable future workers to produce a quicker answer to the questionnaire and to get a better interpretation out of it. Future implications of results are finally discussed (AU)