A new way to target resistant cancer

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Blood cancers, such as leukemia, can be effectively treated with chemotherapy, although relapse usually occurs when resistant cancer cells evade the original drug regimen.

Harvard University researchers have identified a unique characteristic of the resistant cancer cells: a temporary change in metabolism, or how they use nutrients. The findings, published in the journal Cell Metabolism, pave the way for using drugs to target the metabolic pathway and eliminate resistant cells.

“In the cancer field, we usually think about resistance as a concept linked to permanent genetic changes. Our findings show that there are other mechanisms contributing to why some cells survive chemotherapy and others do not — the nutrients they have in their microenvironment and how they use them might matter just as much as the genetic background,” said senior author David Scadden, the Gerald and Darlene Jordan Professor of Medicine and professor of stem cell and regenerative biology.

Resistant cancer cells are rare, so they are difficult to detect after chemotherapy. To identify the cells and track their progression over time, the researchers used a mouse model of acute myeloid leukemia and labeled the cells with a bioluminescent protein and a fluorescent protein. The researchers honed in on the cells at two specific time points.

“We studied the cells when the cancer relapsed, which is normally the point that resistance is studied, because it is clinically obvious,” said lead author Nick van Gastel. “But we also isolated the cells at the point of maximal chemotherapy response, which is basically the moment that you have the fewest cells left. Those are the cells that endured the chemotherapy stress and can now cause relapse.”

The researchers found that the cells left after chemotherapy went through a temporary change in metabolism. Specifically, they changed the way they used the amino acid glutamine, directing it almost exclusively to fuel nucleotide production.

“If you look too late, when the relapse has occurred, these changes are no longer visible,” van Gastel said. “It’s a transient stress response. If you target metabolism during that time, the cancer cells are extremely vulnerable.”

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