Certain nutrients may fuel cancer therapy resistance

Tumors can leverage glucose and acetate to resist targeted therapies directed at specific cellular molecules.

Tumors can leverage glucose and acetate to resist targeted therapies directed at specific cellular molecules, according to scientists studying glioblastoma.

The findings, published in the Proceedings of the National Academy of Sciences (2015; doi:10.1073/pnas.1511759112), demonstrate that nutrients can strongly affect the signaling molecules that drive tumors.

"This study shows that metabolic and nutritional factors might be quite important in cancer development and treatment," said lead author Paul Mischel, MD, a member of the Ludwig Cancer Research Center and Professor of Pathology at the University of California, San Diego.

The study also highlights one way that tumors can evade targeted drugs such as erlotinib and gefitinib, inhibitors of a mutant form of the cellular molecule EGFR (epidermal growth factor receptor) that drives the growth of many glioblastomas and other tumor types.

Cancer researchers have known for years that tumors have unusual metabolisms, because their rapid use of glucose is used as a diagnostic tool for tumors in PET scans. But only recently have scientists begun to flesh out the details of this metabolic shift.

Mischel and other researchers have previously shown that this shift can occur through the activation of a central cellular signal, mTOR complex 2 (mTORC2). mTORC2 is involved in switching cancer cells to a hyperactive metabolic state, prompting the increased influx of glucose and acetate into cancer cells. Glucose and acetate provide fuel and cellular building blocks to perpetuate the rapid growth of tumors.

In the new study, Mischel and his colleagues found that glucose and acetate in turn regulate mTORC2, propelling tumor growth and fending off targeted drugs. "This is a two way street," explained Mischel. "Signaling molecules like mTORC2 can change metabolism, and metabolites can change mTORC2."

The findings first emerged from experiments in glioblastoma cells cultivated in a petri dish. In one experiment, the researchers treated the cells with either glucose or acetate and found that at least one of these nutrients was required in order to turn on mTORC2 in response. The researchers also tested glioblastoma cells with a mutant form of EGFR that turns on mTORC2 and propels tumor growth.

In the absence of glucose and acetate, EGFR inhibitors can switch off mTORC2 signaling. But when the researchers added glucose and acetate, the drugs did not work, and so mTORC2 stayed on and the cells thrived.

Together, the experiments show that glucose or acetate can activate mTORC2 through the production of acetyl-coA, enabling tumors to resist targeted therapies such as EGFR inhibitors. Activated mTORC2 in turn propels tumor growth by regulating metabolism and other cellular processes.

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The findings provide a window into the treatment of glioblastoma, which leaves most newly diagnosed patients with less than 2 years to live. To reduce deadly brain swelling, many patients with glioblastoma require treatment with steroids, which are known to raise blood glucose levels.

The new study suggests that the drugs, which may be necessary to control brain swelling, could also have the paradoxical effect of propelling tumor growth through activation of mTORC2.

Findings in the study also suggest that developing drugs to effectively target mTORC2 may be one avenue to shutting down glioblastoma and possibly other types of tumors.

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