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Br J Cancer. 2017 Apr 25;116(9):1203-1207. doi: 10.1038/bjc.2017.77. Epub 2017 Mar 28.

LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma.

Author information

1
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
2
Department of Hematology/Oncology, Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
3
Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
4
Division of Urologic Oncology, Department of Surgery, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

Abstract

BACKGROUND:

Treatment with tyrosine kinase inhibitors (TKIs) significantly improves survival of patients with renal cell carcinoma (RCC). However, about one-quarter of the RCC patients are primarily refractory to treatment with TKIs.

METHODS:

We examined viability of RCC and endothelial cells treated with low-density lipoprotein (LDL) and/or TKIs. Next, we validated the potential role of PI3K/AKT signalling in LDL-mediated TKI resistance. Finally, we examined the effect of a high-fat/high-cholesterol diet on the response of RCC xenograft tumours to sunitinib.

RESULTS:

The addition of LDL cholesterol increases activation of PI3K/AKT signalling and compromises the antitumour efficacy of TKIs against RCC and endothelial cells. Furthermore, RCC xenograft tumours resist TKIs in mice fed a high-fat/high-cholesterol diet.

CONCLUSIONS:

The ability of renal tumours to maintain their cholesterol homoeostasis may be a critical component of TKI resistance in RCC patients.

PMID:
28350788
PMCID:
PMC5418451
DOI:
10.1038/bjc.2017.77
[Indexed for MEDLINE]
Free PMC Article

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