Editors' ChoiceCancer Metabolism

LDL cholesterol impairs therapy

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Sci. Signal.  09 May 2017:
Vol. 10, Issue 478, eaan5924
DOI: 10.1126/scisignal.aan5924

A diet high in LDL cholesterol may hinder the therapeutic efficacy of tyrosine kinase inhibitors in cancer patients.

Tyrosine kinase inhibitors (TKIs) are used to treat various cancers, either by suppressing tumor cell proliferation or inhibiting the growth of new vasculature (angiogenesis) in the tumor microenvironment. Acquired resistance, such as that caused by new mutations, or TKI-induced adaptive resistance through signaling rewiring is common in many patients. However, a substantial proportion of patients with renal cell carcinoma (RCC) are resistant to primary treatment with TKIs. Naito et al. found that patients’ high-cholesterol diets may be to blame. Cholesterol is an essential component of cells, but cholesterol-rich low-density lipoproteins (LDLs) are associated with various health problems and diseases. In cultured RCC and endothelial cells, application of LDLs activated the proliferation- and survival-associated PI3K-AKT kinase pathway and decreased the cytotoxicity of various TKIs. Inhibiting PI3K or AKT with pharmacological inhibitors or removing cholesterol from lipid rafts with hydroxypropyl-β-cyclodextrin (HPCD) restored TKI sensitivity in LDL-treated cells. In mice, a high-fat, high-cholesterol diet rendered sunitinib (a TKI that targets multiple receptors) ineffective against the growth of RCC xenografts. Tumors from mice on the high-cholesterol diet showed increased activation of AKT compared with those from mice on a normal diet. Interestingly, application of LDLs to cultured RCC cells did not affect their sensitivity to DNA-intercalating chemotherapeutics, such as doxorubicin and docetaxel, suggesting that the effect of LDLs may be specific to TKI-based therapy, but this remains to be tested further. The epidemiological link between cancer and obesity is well established, and LDL-rich diets are also typically associated with obesity. Research findings are inconclusive, however, as to whether dietary cholesterol contributes to an increased risk for cancer. Nonetheless, these findings show that cholesterol-rich LDLs can counteract TKI action and therefore may impair clinical efforts to treat patients, suggesting that dietary regimens should be an essential part of TKI-based treatment plans.

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