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Montero J.C.,University of Salamanca | Seoane S.,University of Salamanca | Ocaa A.,Complejo Hospitalario Universitario Of Albacete | Pandiella A.,University of Salamanca
Oncogene | Year: 2011

The Neuregulins and their receptors, the ErbB/HER subfamily of receptor tyrosine kinases, have critical roles in animal physiology, and their deregulation is frequent in cancer. Here we report the identification of the guanine nucleotide exchange factor, phosphatidylinositol 3,4,5-triphosphate- dependent Rac exchanger 1 (P-Rex1), as a novel mediator in signalling by ErbB/HER receptors. P-Rex1 was formerly described as a phosphoinositide 3-kinase and GΒγ activated protein that regulates Rac function. We define how ErbB/HER receptors regulate P-Rex1 function, which involves dephosphorylation of inhibitory residues, and phosphorylation of activating residues of P-Rex. The net balance resulting from activation of this phosphorylation/dephosphorylation cycle of P-Rex1 favours Rac activation. Molecular and biological studies indicated that P-Rex1 phosphorylation regulated the proliferation of breast cancer cells, and P-Rex1 knockdown affected their migration or invasiveness, as well as their in vivo tumourigenic potential. Moreover, as we found correlation between high P-Rex1 expression and poor patient outcome in breast cancer, P-Rex1 targeting may be therapeutically relevant in cancer. © 2011 Macmillan Publishers Limited All rights reserved.

Montero J.C.,University of Salamanca | Chen X.,University of Salamanca | Ocana A.,Complejo Hospitalario Universitario Of Albacete | Pandiella A.,University of Salamanca
Molecular Cancer Therapeutics | Year: 2012

mTOR is a serine/threonine kinase that acts by binding different sets of proteins forming two complexes, termed mTORC1 and mTORC2. mTOR is deregulated in a substantial proportion of ovarian tumors. Despite the use of drugs directed to mTOR in ongoing clinical trials, the functional relevance of the individual mTORC branches in ovarian cancer is not known. Here, we show that mTORC1 and mTORC2 were constitutively active in ovarian cancer cell lines. Knockdown of raptor or rictor, proteins required for the function of mTORC1 or mTORC2, respectively, resulted in profound inhibition of ovarian cancer cell proliferation. The knockdown of raptor had a more important inhibitory effect than the knockdown of rictor, indicating mTORC1 had a predominant role over mTORC2 in the control of ovarian cancer cell proliferation. Rapamycin decreased the proliferation of ovarian cancer cells, and this was accompanied by inhibition of the phosphorylation of S6, a protein used as readout of mTORC1 function. However, rapamycin had only amarginal effect on the phosphorylation status of 4E-BP1, anothermTORC1 substrate. Therefore, mTORC1 probably controls p4E-BP1 along two distinct pathways, one of them sensitive to rapamycin and another insensitive. The dual PI3K/mTOR inhibitor BEZ235 was more efficient than rapamycin in its inhibitory action on ovarian cancer cell proliferation. Biochemically, BEZ235 completely inhibited pS6, p4E-BP1, and pAkt. Our results suggest that broad-spectrum mTOR inhibitors that block mTORC1 and mTORC2 are more desirable for their clinical development in ovarian cancer than agents exclusively targeting one of the mTOR branches. ©2012 AACR.

Montero J.C.,University of Salamanca | Seoane S.,University of Salamanca | Ocana A.,Complejo Hospitalario Universitario Of Albacete | Pandiella A.,University of Salamanca
Clinical Cancer Research | Year: 2011

Dasatinib is a small molecule tyrosine kinase inhibitor that targets a wide variety of tyrosine kinases implicated in the pathophysiology of several neoplasias. Among the most sensitive dasatinib targets are ABL, the SRC family kinases (SRC, LCK, HCK, FYN, YES, FGR, BLK, LYN, and FRK), and the receptor tyrosine kinases c-KIT, platelet-derived growth factor receptor (PDGFR) α and β, discoidin domain receptor 1 (DDR1), c-FMS, and ephrin receptors. Dasatinib inhibits cell duplication, migration, and invasion, and it triggers apoptosis of tumoral cells. As a consequence, dasatinib reduces tumoral mass and decreases the metastatic dissemination of tumoral cells. Dasatinib also acts on the tumoral microenvironment, which is particularly important in the bone, where dasatinib inhibits osteoclastic activity and favors osteogenesis, exerting a bone-protecting effect. Several preclinical studies have shown that dasatinib potentiates the antitumoral action of various drugs used in the oncology clinic, paving the way for the initiation of clinical trials of dasatinib in combination with standard-of-care treatments for the therapy of various neoplasias. Trials using combinations of dasatinib with ErbB/HER receptor antagonists are being explored in breast, head and neck, and colorectal cancers. In hormone receptor-positive breast cancer, trials using combinations of dasatinib with antihormonal therapies are ongoing. Dasatinib combinations with chemotherapeutic agents are also under development in prostate cancer (dasatinib plus docetaxel), melanoma (dasatinib plus dacarbazine), and colorectal cancer (dasatinib plus oxaliplatin plus capecitabine). Here, we review the preclinical evidence that supports the use of dasatinib in combination for the treatment of solid tumors and describe various clinical trials developed following a preclinical rationale. ©2011 AACR.

Seoane S.,University of Salamanca | Montero J.C.,University of Salamanca | Ocana A.,Complejo Hospitalario Universitario Of Albacete | Pandiella A.,University of Salamanca
Journal of the National Cancer Institute | Year: 2010

Background The receptor tyrosine kinase, HER2, is overexpressed in approximately 25% of patients with breast cancer and is implicated in the aggressiveness of cancer. Targeting of HER2 signaling with trastuzumab, a monoclonal antibody that inhibits HER2 activity, has demonstrated clinical benefits. Methods We investigated whether the antitumor activity of trastuzumab can be potentiated by dasatinib, a small-molecule tyrosine kinase inhibitor, on breast cancer cell lines that overexpress HER2 (BT474 and SKBR3) or have normal HER2 expression (MCF7 and T47D). Functional, biochemical, and gene expression microarray studies were performed to test the effect of trastuzumab, dasatinib, or a combination of trastuzumab and dasatinib on cell proliferation; HER activation; cell cycle; DNA damage; and apoptosis. The effect of drugs on mice (n = 6 per group) bearing xenograft tumors originating from HER2-overexpressing BT474 cells was assessed, and tumors were evaluated for an effect on volume, HER signaling, and DNA damage. All statistical tests were two-sided. Results Trastuzumab and dasatinib combination showed a synergistic effect on the proliferation of HER2-overexpressing breast cancer cells (combination index = 0.44, 95% confidence interval = 0.30 to 0.58). The drug combination also induced a stronger inhibitory effect on HER2 activation than the individual drugs, decreased the level of proteins involved in DNA damage response, induced DNA double-strand breaks, cell cycle arrest, and caspase-independent apoptosis. Mice (n = 6 per group) bearing xenograft tumors originating from HER2-overexpressing BT474 cells showed statistically significantly reduced tumor volume on day 28 when treated with the drug combination (control vs trastuzumab and dasatinib combination; mean volume = 2.6 vs 0.5 cm3, difference = 2.1 cm 3, 95% confidence interval = 0.76 to 3.51 cm3, P =. 01) and total regression of tumors by day 36 with no later relapse. ConclusionsResults showed that HER2 and dasatinib-sensitive tyrosine kinases act in a synergistic manner to safeguard the breast cancer cells from DNA damage. The therapeutic targeting of multikinase inhibition opens new avenues for the treatment of HER2-positive breast cancer patients. © 2010 The Author.

Serena J.,Hospital Universitario Dr Josep Trueta | Segura T.,Complejo Hospitalario Universitario Of Albacete | Roquer J.,Hospital Universitari Del Mar | Garcia-Gil M.,Institute dInvestigacio en Atencio Primaria IDIAP Jordi Gol | Castillo J.,University of Santiago de Compostela
BMC Neurology | Year: 2015

About 20% of patients with a first ischaemic stroke will experience a new vascular event within the first year. The atherosclerotic burden, an indicator of the extension of atherosclerosis in a patient, has been associated with the risk of new cardiovascular events in the general population. However, no predictive models reliably identify groups at a high risk of recurrence. The ARTICO study prospectively analysed the predictive value for the risk of recurrence of specific atherosclerotic markers. Methods: The multicentre ARTICO study included 620 consecutive independent patients older than 60 years suffering from a first non-cardioembolic stroke. We analysed classical stroke risk factors; duplex study of supraaortic trunk including intima-media thickness (IMT) measurement; quantification of internal carotid (ICA) stenosis; number, morphology and surface characteristics of carotid plaques; ankle brachial index (ABI); and the presence of microalbuminuria. Patients were followed up at 6 and 12 months after inclusion. The primary end-point was death or major cardiovascular events. Results: Any vascular event or death at 12 months occurred in 78 (13.8%) patients. In 40 (7.1%) of these the vascular event was a stroke recurrence. Weight, history of diabetes mellitus, history of symptomatic PAD, ABI <0.9 and significant ICA stenosis (>50%) were associated with a higher risk of vascular events on follow-up in the bivariate analysis. Conclusions: Symptomatic PAD identifies a high risk group of vascular recurrence after a first non-cardioembolic stroke. The associated increased risk was particularly high in patients with both ICA stenosis and either symptomatic or asymptomatic PAD. Neither asymptomatic PAD alone nor isolated ICA stenosis >50% were associated with an increased risk of recurrence in this particularly high-risk group of non-cardioembolic stroke. © Serena et al.; licensee BioMed Central.

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