PHILADELPHIA (September 3, 2015) – Drugs that target key proteins involved in cholesterol metabolism could represent a promising new treatment strategy for a broad range of cancers, according to research by Fox Chase Cancer Center investigators. The study, published September 3rd in Cell Reports, reveals that deficiency in the enzymes SC4MOL and NSDHL depletes cancer cells of cholesterol, thereby inhibiting tumor growth in a mouse model of skin cancer. Moreover, treatments that target this cholesterol pathway sensitize cancer cells to the effects of an FDA-approved drug used to treat several types of cancer.
“This knowledge can be used to develop new highly effective therapeutic strategies based on the synergistic activity of drugs targeting cholesterol homeostasis and oncogenic signaling pathways,” said first study author Linara Gabitova, a graduate student at Fox Chase Cancer Center and Kazan Federal University in Russia. “New therapeutic molecules targeting NSDHL/SC4MOL could be discovered, and currently available drugs can be made more effective through new combinations based on the findings of the paper.”
Cholesterol is a key ingredient in the cell membrane and plays an important role in cancer cell signaling. Cancer cells require elevated levels of cholesterol to support their rapid growth, and mutations in a major cancer-causing gene called EGFR help to meet this need by increasing cholesterol synthesis and uptake from the bloodstream. However, tumors are often resistant to EGFR inhibitors, and cholesterol-lowering drugs called statins also have limited effectiveness because cancer cells can compensate by increasing cholesterol synthesis and uptake. “The resistance of tumors to existing cholesterol-lowering therapies highlights the need for novel treatment approaches,” said senior study author Igor Astsaturov MD, PhD, Assistant Professor of Medical Oncology at Fox Chase.
While searching for a solution to this problem, Gabitova and Astsaturov recently discovered that depletion of SC4MOL and NSDHL – enzymes involved in the cholesterol synthesis pathway – sensitizes cancer cells to FDA-approved EGFR inhibitors. But these enzymes are critical for normal embryonic development, leaving it uncertain whether they would be viable drug targets for novel cancer therapies. Moreover, the mechanisms by which these enzymes control cancer cell growth have been unclear.
In the new study, Gabitova and Astsaturov found that inactivation of the Nsdhl gene in the skin cells of adult mice strongly suppressed the growth of skin tumors harboring mutations in the KRAS cancer gene, without producing toxicity in the animals. In head and neck cancer cells, the depletion of SC4MOL and NSDHL led to the activation of a protein called LXR, resulting in the blockade of cholesterol uptake and an increase in cholesterol release into the bloodstream. Moreover, treatment of head and neck cancer cells with LXR-stimulating molecules enhanced the toxic effects of an EGFR inhibitor called erlotinib, demonstrating the promise of combined therapies that inhibit both cholesterol metabolism and a critical signaling pathway that is overactive in the majority of human cancers.
In future studies, the researchers will examine this pathway in more detail by searching for the molecules that activate LXR and thereby deplete cancer cells of cholesterol they need to grow. “Knowing the exact chemical substances would give us a better understanding of the underlying processes and allow for more effective development of anticancer therapeutic strategies,” Gabitova said.
According to the authors, the findings suggest that activation of LXR may be an effective strategy for treating cancers with overactive EGFR-KRAS signaling. What’s more, drugs that target SC4MOL and NSDHL could potentially create a metabolic trap for cancer cells, simultaneously blocking cholesterol synthesis enabled by these enzymes, while depleting existing cholesterol through the downstream effects on LXR activity. By targeting multiple aspects of cholesterol metabolism, this therapeutic approach could potentially overcome the problem of tumor resistance to existing drugs.
“Our findings highlight the key role of the cholesterol pathway in regulating the growth of human cancers,” Astsaturov said. “The fact that we observed similar signaling interactions in KRAS-induced skin tumors extends the relevance of NSDHL-LXR signaling to the oncogenic KRAS, a major cancer causing gene currently not amenable to drug therapy.”