CD36-Mediated Metabolic Rewiring of Breast Cancer Cells Promotes Resistance to HER2-Targeted Therapies

Feng, William W.; Wilkins, Owen M.; Bang, Scott; Ung, Matthew; Li, Jiaqi; An, Jennifer; Genio, Carmen del; Canfield, Kaleigh; DiRenzo, James; Wells, Wendy A.; Gaur, Arti; Robey, Brooks R.B.; Guo, Jessie Yanxiang; Powles, Ryan L.; Sotiriou, Christos; Pusztai, Lajos; Febbraio, Maria; Cheng, Chao; Kinlaw, William W.B.; Kurokawa, Manabu

doi:10.1016/j.celrep.2019.11.008

Cited by 128 publications

(122 citation statements)

References 47 publications

(69 reference statements)

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“…They showed that inhibition of CD36 could selectively suppress the growth of lapatinib resistant but not lapatinib sensitive cells, both in vitro and in mouse models. Deletion of the CD36 gene in a mouse model of breast cancer significantly attenuated mammary tumor development [166]. These results suggest that CD36 along with other FA transporters may play a role in the acquired resistance mechanisms of cancer cells.…”

Section: The Potential Role Of Fatty Acid Metabolism In Mapk Signalinmentioning

confidence: 73%

“…Although glycolysis and mitochondrial metabolism have been extensively studied in cancer and drug resistance, the role of lipid and fatty acid metabolism has become an emerging topic of interest. Feng et al demonstrated the reprogramming from de novo FA synthesis to exogenous FA uptake in acquired HER2 inhibitor resistance in breast cancer [166]. cDNA microarrays indicated the upregulation of the CD36 receptor, a FA transporter, in lapatinib (dual ERBB1/2 inhibitor)-resistant cells.…”

Section: The Potential Role Of Fatty Acid Metabolism In Mapk Signalinmentioning

confidence: 99%

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Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

Lee

Rauch

Kölch

2020

IJMS

489

338

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Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Here, we focus on the role of MAPK pathways in modulating drug sensitivity and resistance in cancer. We briefly discuss new findings in the extracellular signaling-regulated kinase (ERK) pathway, but mainly focus on the mechanisms how stress activated MAPK pathways, such as p38 MAPK and the Jun N-terminal kinases (JNK), impact the response of cancer cells to chemotherapies and targeted therapies. In this context, we also discuss the role of metabolic and epigenetic aberrations and new therapeutic opportunities arising from these changes.

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Section: The Potential Role Of Fatty Acid Metabolism In Mapk Signalinmentioning

confidence: 73%

Section: The Potential Role Of Fatty Acid Metabolism In Mapk Signalinmentioning

confidence: 99%

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

Lee

Rauch

Kölch

2020

IJMS

489

338

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“…Highly aggressive prostate cancers show high expression of CD36 which facilitates the intake of exogenous FAs, and the subsequent LDs mobilization provokes a significant alteration in intracellular lipid content in terms of acyl-carnitines, monoacylglycerols and other lysophospholipids (95). Other findings have found the breast cancer cells resistant to HER2 therapy upregulate CD36, and thus acquiring an increased lipid metabolism and metabolic plasticity, both crucial for promoting resistant cells the adaptation and survival under nutrient deprivation and drug toxicity (96). Also, hypoxic breast and glioblastoma cells cancer cells upload FAs from the TME.…”

Section: Lipidsmentioning

confidence: 99%

Nutritional Exchanges Within Tumor Microenvironment: Impact for Cancer Aggressiveness

et al. 2020

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Neoplastic tissues are composed not only by tumor cells but also by several non-transformed stromal cells, such as cancer-associated fibroblasts, endothelial and immune cells, that actively participate to tumor progression. Starting from the very beginning of carcinogenesis, tumor cells, through the release of paracrine soluble factors and vesicles, i.e., exosomes, modify the behavior of the neighboring cells, so that they can give efficient support for cancer cell proliferation and spreading. A mandatory role in tumor progression has been recently acknowledged to metabolic deregulation. Beside undergoing a metabolic reprogramming coherent to their high proliferation rate, tumor cells also rewire the metabolic assets of their stromal cells, educating them to serve as nutrient donors. Hence, an alteration in the composition and in the flow rate of many nutrients within tumor microenvironment has been associated with malignancy progression. This review is focused on metabolic remodeling of the different cell populations within tumor microenvironment, dealing with reciprocal re-education through the symbiotic sharing of metabolites, behaving both as nutrients and as transcriptional regulators, describing their impact on tumor growth and metastasis.

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“…In this review, we highlight altered lipid metabolism as an emerging mechanism of resistance to small molecule kinase inhibitor therapy in breast cancer cells. Lipid metabolic rewiring is becoming increasingly recognized as a critical mechanism that promotes the growth and survival of cancer cells [12][13][14][15] and is often associated with maintenance of cancer cell stemness [16,17] and development of chemoresistance [17,18] . It is becoming clear that resistance mechanisms to kinase inhibitors in breast cancer often involve PI3K/ AKT/mTOR pathway hyperactivation [8][9][10][11]19] .…”

Section: Introductionmentioning

confidence: 99%

“…Notably, PI3K/AKT/mTOR pathway plays a critical role in the regulation of several lipid metabolic processes such as FA synthesis [20] , FA uptake [21] , FA storage into lipid droplets [22,23] and FAO [24,25] . Recent reports have demonstrated that targeting lipid metabolic pathways may be a valuable therapeutic strategy to re-sensitize cells resistant to HER2-targeted therapies in breast cancer [18,26,27] . We discuss the rationale behind targeting lipid metabolic rewiring in the treatment of drug resistant breast cancer cells as a therapeutic approach that requires further investigation.…”

Section: Introductionmentioning

confidence: 99%

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

Feng¹,

Kurokawa²

2019

CDR

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Breast cancer is one of the leading causes of death in women in the United States. In general, patients with breast cancer undergo surgical resection of the tumor and/or receive drug treatment to kill or suppress the growth of cancer cells. In this regard, small molecule kinase inhibitors serve as an important class of drugs used in clinical and research settings. However, the development of resistance to these compounds, in particular HER2 and CDK4/6 inhibitors, often limits durable clinical responses to therapy. Emerging evidence indicates that PI3K/AKT/mTOR pathway hyperactivation is one of the most prominent mechanisms of resistance to many small molecule inhibitors as it bypasses upstream growth factor receptor inhibition. Importantly, the PI3K/AKT/mTOR pathway also plays a pertinent role in regulating various aspects of cancer metabolism. Recent studies from our lab and others have demonstrated that altered lipid metabolism mediates the development of acquired drug resistance to HER2-targeted therapies in breast cancer, raising an interesting link between reprogrammed kinase signaling and lipid metabolism. It appears that, upon development of resistance to HER2 inhibitors, breast cancer cells rewire lipid metabolism to somehow circumvent the inhibition of kinase signaling. Here, we review various mechanisms of resistance observed for kinase inhibitors and discuss lipid metabolism as a potential therapeutic target to overcome acquired drug resistance.

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CD36-Mediated Metabolic Rewiring of Breast Cancer Cells Promotes Resistance to HER2-Targeted Therapies

Cited by 128 publications

References 47 publications

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

Nutritional Exchanges Within Tumor Microenvironment: Impact for Cancer Aggressiveness

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

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