Predicting Clinical Response to Everolimus in ER+ Breast Cancers Using Machine-Learning

Endocrine therapy remains the primary treatment choice for ER+ breast cancers. However, most advanced ER+ breast cancers ultimately develop resistance to endocrine. This acquired resistance to endocrine therapy is often driven by the activation of the PI3K/AKT/mTOR signaling pathway. Everolimus, a drug that targets and inhibits the mTOR complex has been shown to improve clinical outcomes in metastatic ER+ breast cancers. However, there are no biomarkers currently available to guide the use of everolimus in the clinic for progressive patients, where multiple therapeutic options are available. Here, we utilized gene expression signatures from 9 ER+ breast cancer cell lines and 23 patients treated with everolimus to develop and validate an integrative machine learning biomarker of mTOR inhibitor response. Our results show that the machine learning biomarker can successfully distinguish responders from non-responders and can be applied to identify patients that will most likely benefit from everolimus treatment

The Double-stranded RNA–dependent Protein Kinase Differentially Regulates Insulin Receptor Substrates 1 and 2 in HepG2 Cells

The RNA-dependent protein kinase (PKR), initially known as a virus infection response protein, is found to differentially regulate two major players in the insulin signaling pathway, IRS1 and IRS2. PKR up-regulates the inhibitory phosphorylation of IRS1 and the expression of IRS2 at the transcriptional level

LncRNA Cancer Pharmacogenomics

Datasets and scripts associated with "Discovering long noncoding RNA predictors of anticancer drug sensitivity beyond protein-coding genes". Nath et al. PNAS (2019); 20190999

Emerging role of long non-coding RNAs in cancer precision medicine

A vast majority of the human genome encodes long non-coding RNAs (lncRNAs) as compared to protein-coding genes (PCGs). But most efforts to determine biomarkers of anticancer drug response have focused entirely on PCGs. Comprehensive investigation of lncRNAs and drug response demonstrates that lncRNAs are indeed crucial biomarkers of drug response

ENDORSE: a prognostic model for endocrine therapy in estrogen‐receptor‐positive breast cancers

Abstract Advanced and metastatic estrogen receptor‐positive (ER+) breast cancers are often endocrine resistant. However, endocrine therapy remains the primary treatment for all advanced ER+ breast cancers. Treatment options that may benefit resistant cancers, such as add‐on drugs that target resistance pathways or switching to chemotherapy, are only available after progression on endocrine therapy. Here we developed an endocrine therapy prognostic model for early and advanced ER+ breast cancers. The endocrine resistance (ENDORSE) model is composed of two components, each based on the empirical cumulative distribution function of ranked expression of gene signatures. These signatures include a feature set associated with long‐term survival outcomes on endocrine therapy selected using lasso‐regularized Cox regression and a pathway‐based curated set of genes expressed in response to estrogen. We extensively validated ENDORSE in multiple ER+ clinical trial datasets and demonstrated superior and consistent performance of the model over clinical covariates, proliferation markers, and multiple published signatures. Finally, genomic and pathway analyses in patient data revealed possible mechanisms that may help develop rational stratification strategies for endocrine‐resistant ER+ breast cancer patients

Trigonotis guilielmii A. Gray

原著和名: タチカメバサウ科名: ムラサキ科 = Boraginaceae採集地: 長野県 松本市 袴越山 (信濃 松本市 袴越山)採集日: 1979/6/2採集者: 萩庭丈壽整理番号: JH001328国立科学博物館整理番号: TNS-VS-95132

Synergy analysis reveals association between insulin signaling and desmoplakin expression in palmitate treated HepG2 cells.

The regulation of complex cellular activities in palmitate treated HepG2 cells, and the ensuing cytotoxic phenotype, involves cooperative interactions between genes. While previous approaches have largely focused on identifying individual target genes, elucidating interacting genes has thus far remained elusive. We applied the concept of information synergy to reconstruct a "gene-cooperativity" network for palmititate-induced cytotoxicity in liver cells. Our approach integrated gene expression data with metabolic profiles to select a subset of genes for network reconstruction. Subsequent analysis of the network revealed insulin signaling as the most significantly enriched pathway, and desmoplakin (DSP) as its top neighbor. We determined that palmitate significantly reduces DSP expression, and treatment with insulin restores the lost expression of DSP. Insulin resistance is a common pathological feature of fatty liver and related ailments, whereas loss of DSP has been noted in liver carcinoma. Reduced DSP expression can lead to loss of cell-cell adhesion via desmosomes, and disrupt the keratin intermediate filament network. Our findings suggest that DSP expression may be perturbed by palmitate and, along with insulin resistance, may play a role in palmitate induced cytotoxicity, and serve as potential targets for further studies on non-alcoholic fatty liver disease (NAFLD)

ONC201/TIC10 enhances durability of mTOR inhibitor everolimus in metastatic ER+ breast cancer

The mTOR inhibitor, everolimus, is an important clinical management component of metastatic ER+ breast cancer (BC). However, most patients develop resistance and progress on therapy, highlighting the need to discover strategies that increase mTOR inhibitor effectiveness. We developed ER+ BC cell lines, sensitive or resistant to everolimus, and discovered that combination treatment of ONC201/TIC10 with everolimus inhibited cell growth in 2D/3D in vitro studies. We confirmed increased therapeutic response in primary patient cells progressing on everolimus, supporting clinical relevance. We show that ONC201/TIC10 mechanism in metastatic ER+ BC cells involves oxidative phosphorylation inhibition and stress response activation. Transcriptomic analysis in everolimus resistant breast patient tumors and mitochondrial functional assays in resistant cell lines demonstrated increased mitochondrial respiration dependency, contributing to ONC201/TIC10 sensitivity. We propose that ONC201/TIC10 and modulation of mitochondrial function may provide an effective add-on therapy strategy for patients with metastatic ER+ BCs resistant to mTOR inhibitors