Lipid metabolic reprogramming as an emerging mechanism of resistance to kinase inhibitors in breast cancer

Feng, William W.; Kurokawa, Manabu

doi:10.20517/cdr.2019.100

Cited by 25 publications

(18 citation statements)

References 161 publications

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“…It should be noted that other drivers of fatty acid biosynthesis include key enzymes such as acetyl CoA carboxylase (ACC) and ATP citrate lyase (ACLY) [32,33], thus additional studies will be required to determine if increased fatty acid metabolism occurs in 223/ pR cells via upregulation of these enzymes. Lipid metabolic rewiring is an emerging mechanism of resistance to many targeted therapies in breast cancer [34]. Several groups have demonstrated that lipid reprogramming promotes the growth and survival of cancer cells and often correlates with cancer cell stemness and resistance to therapy [35][36][37][38][39][40].…”

Section: Discussionmentioning

confidence: 99%

Differential gene expression analysis of palbociclib-resistant TNBC via RNA-seq

Lanceta

Lypova

O’Neill

et al. 2021

Breast Cancer Res Treat

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Purpose The management of triple-negative breast cancer (TNBC) remains a significant clinical challenge due to the lack of effective targeted therapies. Inhibitors of the cyclin-dependent kinases 4 and 6 (CDK4/6) are emerging as promising therapeutic agents against TNBC; however, cells can rapidly acquire resistance through multiple mechanisms that are yet to be identified. Therefore, determining the mechanisms underlying resistance to CDK4/6 inhibition is crucial to develop combination therapies that can extend the efficacy of the CDK4/6 inhibitors or delay resistance. This study aims to identify differentially expressed genes (DEG) associated with acquired resistance to palbociclib in ER− breast cancer cells. Methods We performed next-generation transcriptomic sequencing (RNA-seq) and pathway analysis in ER− MDA-MB-231 palbociclib-sensitive (231/pS) and palbociclib-resistant (231/pR) cells. Results We identified 2247 up-regulated and 1427 down-regulated transcripts in 231/pR compared to 231/pS cells. DEGs were subjected to functional analysis using Gene Ontology (GO) and the KEGG database which identified many transduction pathways associated with breast cancer, including the PI3K/AKT, PTEN and mTOR pathways. Additionally, Ingenuity Pathway Analysis (IPA) revealed that resistance to palbociclib is closely associated with altered cholesterol and fatty acid biosynthesis suggesting that resistance to palbociclib may be dependent on lipid metabolic reprograming. Conclusion This study provides evidence that lipid metabolism is altered in TNBC with acquired resistance to palbociclib. Further studies are needed to determine if the observed lipid metabolic rewiring can be exploited to overcome therapy resistance in TNBC.

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Section: Discussionmentioning

confidence: 99%

Differential gene expression analysis of palbociclib-resistant TNBC via RNA-seq

Lanceta

Lypova

O’Neill

et al. 2021

Breast Cancer Res Treat

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“…In this scenario, lipid metabolic reprogramming is a hallmark in cancer [ 10 , 11 ]. Cancer cells exhibit a “lipogenic phenotype” characterized by exacerbated levels of fatty acid biogenesis, even in the presence of abundant circulating exogenous fatty acids and reflected in the overexpression and increased activity of lipogenic enzymes [ 11 , 12 , 13 , 14 ]. Fatty acids or derived lipid species are then critical for lipid synthesis and membrane structures, protein modification and localization functions, and receptor localization and signaling of major oncogenic signaling pathways [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Expanding Roles of De Novo Lipogenesis in Breast Cancer

Simeone

Tacconi

Longo

et al. 2021

IJERPH

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In recent years, lipid metabolism has gained greater attention in several diseases including cancer. Dysregulation of fatty acid metabolism is a key component in breast cancer malignant transformation. In particular, de novo lipogenesis provides the substrate required by the proliferating tumor cells to maintain their membrane composition and energetic functions during enhanced growth. However, it appears that not all breast cancer subtypes depend on de novo lipogenesis for fatty acid replenishment. Indeed, while breast cancer luminal subtypes rely on de novo lipogenesis, the basal-like receptor-negative subtype overexpresses genes involved in the utilization of exogenous-derived fatty acids, in the synthesis of triacylglycerols and lipid droplets, and fatty acid oxidation. These metabolic differences are specifically associated with genomic and proteomic changes that can perturb lipogenic enzymes and related pathways. This behavior is further supported by the observation that breast cancer patients can be stratified according to their molecular profiles. Moreover, the discovery that extracellular vesicles act as a vehicle of metabolic enzymes and oncometabolites may provide the opportunity to noninvasively define tumor metabolic signature. Here, we focus on de novo lipogenesis and the specific differences exhibited by breast cancer subtypes and examine the functional contribution of lipogenic enzymes and associated transcription factors in the regulation of tumorigenic processes.

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“…SREBP-2 uses LDLR as a carrier to take up cholesterol in the blood, and to activate the key enzyme in the cholesterol synthesis pathway [3-hydroxyglutaryl-coenzyme A (HMG-CoA) reductase] to enhance cholesterol synthesis ( 64 ). The uptake and enhancement of gastric cancer cells will eventually fulfill the need of continuously expanding gastric cancer cells for lipids ( 65 ). Then, inhibitors of the PI3K/Akt/mTOR signaling pathway play an important role in gastric cancer treatment.…”

Section: The Role Of Pi3k/akt/mtor Pathways In Lipid Metabolism In Gastric Cancermentioning

confidence: 99%

Aberrant lipid metabolism reprogramming and immune microenvironment for gastric cancer: a literature review

Cui¹,

Yi²,

Zhu³

et al. 2021

Transl Cancer Res TCR

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Objective: We summarize the aberrant lipid metabolism disorders associated with enzyme activity and expression changes and related immune microenvironment for gastric cancer.Background: Gastric cancer is a malignant tumor of the primary digestive system with high incidence, poor prognosis characterized by extensive metastasis and poor effect with radiotherapy and chemotherapy.One of the most important metabolic characteristics of cancer cells is lipid metabolism reprogramming to adapt to the tumor micro-environment. Methods:The focus of research in recent years has also been on lipid metabolism disorders, particularly aberrant metabolism of fatty acids (FAs) in gastric cancer cells, as well as an upregulation of the expression and activity of key enzymes in lipid metabolism. These changes remind us of the occurrence and development of gastric cancer. These metabolic changes are not unique to cancer cells. Changes in metabolic procedures also determine the function and viability of immune cells. In the immune microenvironment of gastric cancer, the metabolic competition and interaction between cancer cells and immune cells are not very clear, while a deeper understanding of the topic is critical to targeting the differential metabolic requirements of them that comprise an immune response to cancer offers an opportunity to selectively regulate immune cell function.Conclusions: Recent research suggests that targeting metabolism is an emerging and potentially promising treatment strategy for gastric cancer patients. We need to explore it further.

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Lipid metabolic reprogramming as an emerging mechanism of resistance to kinase inhibitors in breast cancer

Cited by 25 publications

References 161 publications

Differential gene expression analysis of palbociclib-resistant TNBC via RNA-seq

Differential gene expression analysis of palbociclib-resistant TNBC via RNA-seq

Expanding Roles of De Novo Lipogenesis in Breast Cancer

Aberrant lipid metabolism reprogramming and immune microenvironment for gastric cancer: a literature review

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