Impact of statin use on cancer-specific mortality and recurrence

Yang, Jing; Li, Chunyu; Shen, Ying; Zhou, Hong; Shao, Yueqin; Zhu, Wei; Chen, Yan

doi:10.1097/md.0000000000019596

Cited by 19 publications

(19 citation statements)

References 96 publications

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“…In addition, pre-clinical data have demonstrated that statins reduce prenylation, a required step in localization and activity of RAS proteins. Statins have therefore been explored in various human disease paradigms that involve deregulation of RAS/MAPK and related signaling axes ( Youssef et al., 2002 ; Davies et al., 2016 ; Yang et al., 2020 ). Importantly, we found that, for some RASopathy variants, the efficacy of some drugs including statins correlated with suppression of pathways outside the canonical RAS pathway.…”

Section: Discussionmentioning

confidence: 99%

Drosophila RASopathy models identify disease subtype differences and biomarkers of drug efficacy

et al. 2021

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Summary RASopathies represent a family of mostly autosomal dominant diseases that are caused by missense variants in the rat sarcoma viral oncogene/mitogen activated protein kinase (RAS/MAPK) pathway including KRAS, NRAS, BRAF, RAF1, and SHP2. These variants are associated with overlapping but distinct phenotypes that affect the heart, craniofacial, skeletal, lymphatic, and nervous systems. Here, we report an analysis of 13 Drosophila transgenic lines, each expressing a different human RASopathy isoform. Similar to their human counterparts, each Drosophila line displayed common aspects but also important differences including distinct signaling pathways such as the Hippo and SAPK/JNK signaling networks. We identified multiple classes of clinically relevant drugs—including statins and histone deacetylase inhibitors—that improved viability across most RASopathy lines; in contrast, several canonical RAS pathway inhibitors proved less broadly effective. Overall, our study compares and contrasts a large number of RASopathy-associated variants including their therapeutic responses.

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Section: Discussionmentioning

confidence: 99%

Drosophila RASopathy models identify disease subtype differences and biomarkers of drug efficacy

et al. 2021

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“…In addition, pre-clinical data has demonstrated that statins reduce prenylation, a required step in localization and activity of RAS proteins. Statins have therefore been explored in various human disease paradigms that involve deregulation of RAS/MAPK and related signaling axes (Davies et al, 2016; Yang et al, 2020; Youssef et al, 2002). Importantly, we found that, for some RASopathy variants, the efficacy of some drugs including statins correlated with suppression of pathways outside the canonical RAS pathway.…”

Section: Discussionmentioning

confidence: 99%

Drosophila RASopathy Models Identify Disease Subtype Differences and Biomarkers of Drug Efficacy

Das

Gatto

Mirmira

et al. 2020

Preprint

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RASopathies represent a family of mostly autosomal dominant diseases that are caused by missense variants in the RAS/MAPK pathway. In aggregate, they are among the more common Mendelian disorders. They share overlapping pathologies that include structural birth and developmental defects that affect the heart, craniofacial and skeletal, lymphatic, and nervous systems. Variants in different genes--including those encoding KRAS, NRAS, BRAF, RAF1, and SHP2--are associated with overlapping but distinct phenotypes. Here, we report an analysis of 13 Drosophila transgenic lines, each expressing a different human disease isoform associated with a form of RASopathy. Similar to their human counterparts, each Drosophila line has common aspects but also important phenotypic distinctions including signaling pathways as well as response to therapeutics. For some lines, these differences represent activation of pathways outside the core RAS signaling pathway including the Hippo and SAPK/JNK signaling networks. We identified two classes of clinically relevant drugs, statins and histone deacetylase inhibitors, that improved viability across most RASopathy lines; in contrast, several canonical RAS pathway inhibitors proved poorly effective against, e.g., SHP2-expressing lines encoded by PTPN11. Our study provides a whole animal platform for comparison of a large number of RASopathy-associated variants. Among these variants we have identified differences in tissue phenotypes, in activation signaling pathways in biomarkers of disease progression and drug efficacy, and suggest drug classes that can be tolerated over long treatment periods for consideration in broad RASopathy trials.

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“…In addition, CD36 inhibition in ovarian cancer cells reduced their in vitro and in vivo invasive capabilities sustained by CAAs (180). Moreover, Masko et al pointed out that the combination of standard treatments with drugs interfering with adipocyte metabolism, like statins, has promising therapeutic relevance in prostate cancer treatment (181,182). The administration of a high fat diet, instead of a normal one, in mice treated with diethylnitrosamine promoted hepatocellular carcinoma development, increasing STAT3 activation and IL-6 production.…”

Section: Adipocyte-released Factors Strengthening Csc Chemotherapy Rementioning

confidence: 99%

Messing Up the Cancer Stem Cell Chemoresistance Mechanisms Supported by Tumor Microenvironment

et al. 2021

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Despite the recent advances in cancer patient management and in the development of targeted therapies, systemic chemotherapy is currently used as a first-line treatment for many cancer types. After an initial partial response, patients become refractory to standard therapy fostering rapid tumor progression. Compelling evidence highlights that the resistance to chemotherapeutic regimens is a peculiarity of a subpopulation of cancer cells within tumor mass, known as cancer stem cells (CSCs). This cellular compartment is endowed with tumor-initiating and metastasis formation capabilities. CSC chemoresistance is sustained by a plethora of grow factors and cytokines released by neighboring tumor microenvironment (TME), which is mainly composed by adipocytes, cancer-associated fibroblasts (CAFs), immune and endothelial cells. TME strengthens CSC refractoriness to standard and targeted therapies by enhancing survival signaling pathways, DNA repair machinery, expression of drug efflux transporters and anti-apoptotic proteins. In the last years many efforts have been made to understand CSC-TME crosstalk and develop therapeutic strategy halting this interplay. Here, we report the combinatorial approaches, which perturb the interaction network between CSCs and the different component of TME.

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Impact of statin use on cancer-specific mortality and recurrence

Cited by 19 publications

References 96 publications

Drosophila RASopathy models identify disease subtype differences and biomarkers of drug efficacy

Drosophila RASopathy models identify disease subtype differences and biomarkers of drug efficacy

Drosophila RASopathy Models Identify Disease Subtype Differences and Biomarkers of Drug Efficacy

Messing Up the Cancer Stem Cell Chemoresistance Mechanisms Supported by Tumor Microenvironment

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