Eicosapentaenoic acid in combination with EPHA2 inhibition shows efficacy in preclinical models of triple-negative breast cancer by disrupting cellular cholesterol efflux

Torres-Adorno, Angie M.; Vitrac, Heidi; Qi, Yuan; Tan, Lin; Levental, Kandice R.; Fan, Yang; Yang, Peiying; Chapkin, Robert S.; Eckhardt, Bedrich L.; Ueno, Naoto T.

doi:10.1038/s41388-018-0569-5

Cited by 32 publications

(49 citation statements)

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“…We found ABCA1 expressed in doxorubicin-sensitive osteosarcoma cells, in line with previous findings showing a constitutive expression of ABCA1 in doxorubicin-sensitive triple-negative breast cancer cells [37]. Unexpectedly, in osteosarcoma cells with acquired resistance to doxorubicin and high levels of ABCB1, the amount of ABCA1 was reduced.…”

Section: Discussionsupporting

confidence: 92%

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

Belisario

Akman

Godel

et al. 2020

Cells

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The ATP Binding Cassette transporter B1 (ABCB1) induces chemoresistance in osteosarcoma, because it effluxes doxorubicin, reducing the intracellular accumulation, toxicity, and immunogenic cell death induced by the drug. The ATP Binding Cassette transporter A1 (ABCA1) effluxes isopentenyl pyrophosphate (IPP), a strong activator of anti-tumor Vγ9Vδ2 T-cells. Recruiting this population may represent an alternative strategy to rescue doxorubicin efficacy in ABCB1-expressing osteosarcoma. In this work, we analyzed how ABCA1 and ABCB1 are regulated in osteosarcoma, and if increasing the ABCA1-dependent activation of Vγ9Vδ2 T-cells could be an effective strategy against ABCB1-expressing osteosarcoma. We used 2D-cultured doxorubicin-sensitive human U-2OS and Saos-2 cells, their doxorubicin-resistant sublines (U-2OS/DX580 and Saos-2/DX580), and 3D cultures of U-2OS and Saos-2 cells. DX580-sublines and 3D cultures had higher levels of ABCB1 and higher resistance to doxorubicin than parental cells. Surprisingly, they had reduced ABCA1 levels, IPP efflux, and Vγ9Vδ2 T-cell-induced killing. In these chemo-immune-resistant cells, the Ras/Akt/mTOR axis inhibits the ABCA1-transcription induced by Liver X Receptor α (LXRα); Ras/ERK1/2/HIF-1α axis up-regulates ABCB1. Targeting the farnesylation of Ras with self-assembling nanoparticles encapsulating zoledronic acid (NZ) simultaneously inhibited both axes. In humanized mice, NZ reduced the growth of chemo-immune-resistant osteosarcomas, increased intratumor necro-apoptosis, and ABCA1/ABCB1 ratio and Vγ9Vδ2 T-cell infiltration. We suggest that the ABCB1 high ABCA1 low phenotype is indicative of chemo-immune-resistance. We propose aminobisphosphonates as new chemo-immune-sensitizing tools against drug-resistant osteosarcomas.

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Section: Discussionsupporting

confidence: 92%

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

Belisario

Akman

Godel

et al. 2020

Cells

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“…Cancer cells should not be assumed to always require high cholesterol levels, nor should any anti-tumour strategy be assumed to necessarily limit cholesterol biosynthesis: exceptions can exist. For instance, inhibition of Ephrin type-A receptor 2 impairs ABCA1 function and decreases cholesterol efflux, thus resulting in membrane rigidity and cell apoptosis in triple-negative breast cancer cells 108 . Similarly, in a mouse model of hepatocellular carcinoma, a cholesterol-rich diet raises membrane cholesterol levels, and consequently increases CD44 relocation into membrane lipid rafts and decreases the interaction between CD44 and the actin-binding protein Ezrin, thus restricting metastasis 109 .…”

Section: Enhancement Of Cd8 T Cell Function and Inhibition Of The Regmentioning

confidence: 99%

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

2020

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C holesterol is vital for the survival and growth of mammalian cells. More than a membrane constituent, cholesterol is a precursor to bile acids and steroid hormones, which can initiate or promote colon, breast and prostate cancers 1-3 . Cholesterol can also modulate signalling pathways involved in tumourigenesis and cancer progression by covalently modifying proteins including hedgehog and smoothened 4,5 , and by facilitating the formation of specialized membrane microdomains 6,7 . Brief overview of cholesterol metabolismEvery mammalian cell can synthesize cholesterol through the mevalonate pathway (Fig. 1a). Two acetyl-CoA molecules in the cytosol condense, thus forming acetoacetyl-CoA, which reacts with the third acetyl-CoA and yields 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). HMG-CoA is reduced to mevalonate by HMG-CoA reductase (HMGCR), the primary rate-limiting enzyme in cholesterol biosynthesis. A series of enzymatic reactions convert mevalonate to farnesyl pyrophosphate (FPP), a precursor of sterols and all non-sterol isoprenoids. The condensation of two FPP molecules to squalene commits the process to sterol production. FPP also gives rise to geranylgeranyl pyrophosphate (GGPP), and both FPP and GGPP can prenylate and activate several oncogenic proteins such as Ras 8 . Squalene is then oxidized by squalene epoxidase (SQLE) to 2,3-epoxysqualene, which is cyclized to lanosterol. In the next steps, lanosterol follows the Bloch pathway, the Kandutsch-Russell pathway or a hybrid pathway before it is finally converted to cholesterol.Beyond de novo cholesterol biosynthesis, most cells acquire cholesterol from low-density lipoprotein (LDL) taken up from the circulation via LDL receptor (LDLR)-mediated endocytosis 9 . Enterocytes absorb dietary cholesterol from the intestinal lumen in a process involving the cholesterol transporter NPC1L1, the clathrin adaptor NUMB and the adaptor protein LIMA1 (refs. 10-12 ). Cholesterol within the cell is dynamically transported, reaching the destined membranes for structural and functional needs 13 . Cholesterol in excess of the current cellular demand is either exported from the cell by ATP-binding cassette (ABC) transporters, Reprogrammed cholesterol metabolism in cancer cellsHallmark features of cancer cholesterol metabolism. As fastproliferating cells, cancer cells require high levels of cholesterol for membrane biogenesis and other functional needs. For example, the cholesterol-derived oncometabolite 6-oxo-cholestan-3β,5α-diol, which is enriched in patients with breast cancer, binds glucocorticoid receptors and subsequently promotes tumour growth 19 . In general, cholesterol metabolism substantially contributes to cancer progression, including cell proliferation, migration and invasion 20-23 .Cholesterol metabolism produces essential membrane components as well as metabolites with a variety of biological functions. In the tumour microenvironment, cell-intrinsic and cell-extrinsic cues reprogram cholesterol metabolism and consequently promote tumourigenesis. Cholesterol-de...

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“…Moreover, our results revealed a possibility of personalized immunotherapy approach combined with EPHA inhibitor in NSCLC, for the optimization of ICI treatment in clinical practice in further. 38 However, this needs to be further studied.…”

Section: Discussionmentioning

confidence: 99%

EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma

Bai

Duan

et al. 2020

J Immunother Cancer

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BackgroundEphrin type-A receptors (EPHA) are members of family of receptor tyrosine kinases and are related to tumor immunogenicity and immune microenvironment, however, the association between EPHA mutation (EPHAmut) and efficacy of immune checkpoint inhibitors (ICIs) has not been investigated in non-small cell lung cancer (NSCLC).MethodsMultiple cohorts were used to assess the immunotherapeutic predictive performance of EPHAmut, including one discovery cohort (n=79) and two public validation cohort (cohort 1: NSCLC, n=165; cohort 2: pan-cancer, n=1662). The Cancer Genome Atlas cohort was used for prognostic analysis and mechanism exploration.ResultsIn the discovery cohort, patients with EPHAmut had superior disease control rate (72.2% vs 36.1%, p=0.01) and progression-free survival (PFS) (HR 0.38; 95% CI 0.21 to 0.68; p<0.001) compared with those with wide-type EPHA (EPHAwt) in NSCLC. The association between EPHAmut and immunotherapy outcomes in NSCLC was consistently observed in the validation cohorts by multivariable models (cohort 1, PFS HR 0.59; 95% CI 0.37 to 0.96; p=0.03; cohort 2, overall survival (OS) HR 0.63; 95% CI 0.41 to 0.98; p=0.04). Further pooled estimates of the discovery and validation cohorts showed that patients with EPHAmut exhibited a significantly longer PFS and OS in lung adenocarcinoma (LUAD) while not squamous cell lung cancer (LUSC). Consistently, mechanism analysis revealed that patients with EPHAmut was associated with increased T cell signatures and downregulated transforming growth factor-β signaling compared with patients with EPHAwt in LUAD while not LUSC.ConclusionsOur results demonstrated that EPHAmut is an independent classifier that could stratify patients with LUAD for ICIs therapy. Further prospective studies are warranted.Trial registration numberNCC2016JZ-03, NCC2018-092.

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Eicosapentaenoic acid in combination with EPHA2 inhibition shows efficacy in preclinical models of triple-negative breast cancer by disrupting cellular cholesterol efflux

Cited by 32 publications

References 49 publications

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

ABCA1/ABCB1 Ratio Determines Chemo- and Immune-Sensitivity in Human Osteosarcoma

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma

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