Advanced malignant melanoma is one of the most lethal cancers, because it is highly metastatic and refractory to conventional chemotherapy. About 60% of melanomas harbor oncogenic BRAF mutations which aberrantly activate MEK/ERK signaling pathway. BRAF and MEK inhibitors have been shown efficacious in patients with BRAF-mutant melanoma, but there is not effective target therapy for BRAF wild type melanomas. Unfortunately acquired resistance to BRAF targeted therapies is a common event: 50% of treated patients progressed within 6 to 7 months after the initiation of treatment. Resistance is associated with reactivation of the MAPK pathway (through development of de novo NRAS, NF1 or MEK mutations) or activation of parallel pathways, such as the PI3K/AKT pathway. Cancer stem cells (CSCs) represent a subpopulation of tumor cells that possess self-renewal and tumor initiation capacity. It has been postulated that CSC could be linked to acquired resistance to both conventional and targeted therapies. Salinomycin, an ionophore antibiotic, has been shown to selectively kill CSCs in several types of human cancers, most likely by interfering with ABC drug transporters, the Wnt/β-catenin signaling pathway, and other CSC pathways. In this study, we have analyzed a wide panel of human melanoma cell lines with a known mutational status of BRAF, tumor suppressors, and other frequently mutated oncogenes in melanoma, and their sensibility to several protein kinase inhibitors (PKIs) in vitro, including the BRAF inhibitor vemurafenib. We have combined these PKIs with the CSC inhibitor, salinomycin, in order to find therapeutically relevant synergies. To better characterize CSC phenotype, we carried out tumorsphere formation assays in vitro, FACS analysis of CSC canonical markers, to find that salinomycin sensitizes BRAF-wild type melanoma cell lines to the cytotoxic effect of particular PKIs. Importantly, we demonstrated that salinomycin-PKI combination therapy supresses the emergence of vemurafenib-resistant subpopulations in BRAF-mutant melanoma cell lines. Overall, we find that targeting CSC property of wild-type BRAF inhibitor with salinomycin significantly potentiates therapeutic activity of PKIs. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A292. Citation Format: Daniel Crespo, Ines Pulido, Maria L. Rodriguez, Salvador Aparisi, Alejandro Lopez, Margaret Soucheray, Fatima Al-Shahrour, Takeshi Shimamura, Angel Ortega, Julian Carretero. Salinomycin, an anti-cancer stem cell antibiotic, overcomes acquired resistance to BRAF inhibitors in BRAF-mutant human melanoma cell lines. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A292.
Epigenetic changes are involved in the onset and progression of cancer, and the detection of DNA methylation signatures may foster the improvement of diagnosis and prognosis. While the emergence of innovative technologies has fostered numerous studies in breast cancer, many lack statistical power due to the small sample sizes generally involved. In this study, we present a novel meta-analysis that identifies a common pattern of DNA methylation in all breast cancer subtypes. We obtained DNA methylation signatures at the gene and biological function level, identifying those significant groups of genes and functional pathways affected. To achieve this, we conducted a thorough systematic review following PRISMA statement guidelines for the selection of studies on DNA methylation in breast cancer. In total, we gathered four studies (GSE52865, GSE141338, GSE59901 and GSE101443) that were split into 13 comparisons comprising a set of 144 individuals. We discovered that most breast cancer subtypes share a significant deregulation in the immune system and alterations to the cell cycle. This integrative approach combines all available information from public data repositories and possesses greater statistical power than any individual study. Further evaluations of the identified differential biological processes and pathways may support the identification of novel biomarkers and therapeutic targets.
Lung cancer is the leading cause of cancer deaths in western countries, and adenocarcinomas (LADs) are the most frequent histological subtype. The aberrant activation of the kinases promotes plethora of tumorigenic processes, mainly through PI3K and MAPK oncogenic pathways leading to oncogene addiction. The activation of PI3K pathway deregulates mTOR, a master kinase for cell growth and autophagy. Autophagy can be pro- or anti- tumorigenic, however its roles in protecting tumors exposed to metabolic stress under chemotherapy are considered as a survival mechanism for the tumors leading to acquired resistance. Consequently, the inhibition of autophagy is an attractive therapy to prevent the emergence of acquired resistance. Activating mutations in EGFR and KRAS are mutually exclusive and are the most frequent oncogene activation in LAD. There are considerable differences in the control of signalling pathways including PI3K-mTOR axis. Therefore, it is hypothesized that the susceptibility to autophagy differs depending on EGFR or KRAS mutational status. To test the hypothesis, we applied nutrient-starvation conditions, the most well-known inducer of autophagy, to a panel of LAD cell lines bearing known EGFR or KRAS mutations. As a positive control, cells were treated with rapamycin, which also induced autophagy inhibiting MTOR activity. Autophagy activation was analyzed by: i) Western blot of LC3-II and p62/SQSTM1 protein levels, that measures autophagy flux and autophagic protein degradation, respectively; and ii) autophagolysosome detection and lysosomal activity by fluorescent microscopy. Our data suggest that KRAS-mutant LAD cell lines are able to activate autophagy, whereas EGFR-mutant are not, under starvation stress. Furthermore, we found a potential interaction between mutant EGFR and Beclin 1 (BECN1, a protein required for the initiation of the autophagosome) at the cell membrane proximity, using co-immunolocalization by confocal microscopy and immunoprecipitation followed by Western blot. Together, these data provide a compelling rationale to investigate anti-autophagy therapy in mutant KRAS LADs and warrant further investigation in the regulation of autophagy via a novel link between Beclin1 and mutant EGFR. Citation Format: Maria L. Rodriguez, Ines Pulido, Margaret Soucheray, Daniel Crespo, Fatima Al-shahrour, Takeshi Shimamura, Angel Ortega, Julian Carretero. Differential autophagy activation in KRAS and EGFR mutant lung adenocarcinomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1690. doi:10.1158/1538-7445.AM2013-1690
Epidemiological, clinical and laboratory studies have demonstrated that solar ultraviolet (UV) radiation is the main cause of nonmelanoma skin cancer (i.e., basal cell and squamous cell carcinoma) and it is also a prime factor in the etiology of cutaneous melanoma. The cancer-causing effects of solar exposure on the skin are mainly produced by UV-B radiation in the 290- to 320-nm range, the same range that produces burning in human skin (erythema), inflammation, oxidative stress, DNA damage, etc. Thus, and considering the alarming numbers of skin cancers being diagnosed around the world, it is increasingly evident the need of an effective protection against UV radiation. Polyphenols (PFs) are abundant in many fruits and vegetables, wine, tea, and various dietary supplements. The role of these natural molecules as potential anticarcinogens and photoprotectors has been postulated (e.g. Clifford JL & DiGiovanni J. Cancer Prev Res 3: 132-5, 2010). Resveratrol (trans-3,5,4′-trihydroxystilbene; RES) is a phytoalexin present in a wide variety of plant species, where its synthesis is induced by stress conditions. The cancer chemopreventive activity of RES was first reported by Jang et al [Science 275, 218 - 220 (1997)] in a model of skin carcinogenesis where topic administration of this polyphenol inhibited multistage mouse skin carcinogenesis. Equally promising action is exerted by resveratrol analogues, mainly pterostilbene (3,5-dimethoxy-4′-hydroxy-transstilbene: PTER), which shows a higher half-life and more potent anticancer effects in vivo than RES. The long-term UV-B administration (180 mJ/cm2; 3 doses/week; for a total of 30 weeks) reproduces, in an animal model, which are the consequences in humans of receiving chronic UV-B radiations. We observed that pretreatment of the skin with PTER prevented UV-B-induced skin tumorigenesis (∼90 % of tumor free-mice at the end of treatment, n=20; P<0.01). Our aim was to study the key molecular mechanisms involved in this strong anticancer effect elicited by PTER. Our results indicate that PTER efficiently avoid skin carcinogenesis induced by solar radiation by decreasing DNA mutagenesis, and protein and lipid oxidation. Citation Format: Angel Ortega, Maria L. Rodriguez, Joan A. Sirerol, Ines Pulido, Daniel Crespo, Julian Carretero, Miguel A. Asensi, Salvador Mena, Jose M. Estrela. Pterostilbene exerts full protection against UVB-induced skin carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1280. doi:10.1158/1538-7445.AM2013-1280
Targeted therapy using EGFR tyrosine kinase inhibitor (TKI) is a standard therapy for a subset of non-small cell lung cancer (NSCLC) patients with lung adenocarcinomas (LADs) harboring EGFR kinase domain mutations; however, EGFR TKI therapy shows limited efficacy due to de novo and acquired resistance. Consequently, formulating strategies to potentiate the efficacy of EGFR TKI is of great interest. In EGFR TKI sensitive cells harboring EGFR mutation, it has been shown that EGFR inhibition induces autophagy to protect the cells from metabolic stress. Hydroxychloroquine (HQ), an inhibitor of autophagy, has been shown to potentiate EGFR TKIs in preclinical models, however, preliminary results from recent phase II clinical trials shows no added benefits to the development of resistance to erlotinib in patients with EGFR mutant NSCLC. The result suggests additional layers of mechanisms in controlling autophagy in EGFR mutated NSCLC. Furthermore, little is known about genomic alterations affecting these autophagy genes in lung cancer samples. The meta-analysis of The Cancer Genome Atlas (TCGA) database shows that essential genes for autophagic flux such as ATG5 and ATG7 tend to reduce their expression levels and/or are deleted in a significant proportion of LAD patients, suggesting a more complex scenario where the presence of these genetic alterations may lead to a structurally deficient autophagy. Besides, the detailed CNV analysis of the Cancer Cell Line Encyclopedia (CCLE) dataset suggests that a small subset of NSCLC cell lines may have lost ATG7 locus at chromosome 3. Our validation study showed that, as expected, EGFR-mutant H1650 cells exhibit an intragenic deletion at ATG7 and lack of protein expression. Moreover, functional assays of autophagic flow by western blot and confocal microscopy demonstrated that ATG7-deficient H1650 cells are not able to activate autophagy, whereas infection with lentivirus expressing ectopic ATG7 reconstituted autophagic flux and sensitivity to autophagy inhibitors including HQ. Taken together, our results suggest that genomic biomarkers based on autophagy genes could allow stratification of tumors, and selection of those candidates who could benefit from anti-autophagy therapy. Citation Format: Ines Pulido, Juan L. Pascual, Margaret Soucheray, Maria L. Rodriguez, Daniel T. Crespo, Salvador Aparisi, Joan A. Sirerol, Salvador Mena, Javier Pereda, Fatima Al-shahrour, Angel L. Ortega, Takeshi Shimamura, Julian Carretero. Genomic alterations of autophagy genes disrupts autophagic flux in human lung adenocarcinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 753. doi:10.1158/1538-7445.AM2015-753
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