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Using math to unravel shared drug resistance in cancer cells

Reposted from the College of Science.

A new study involving University of Utah mathematicians produced the surprising result that therapy resistance in breast cancer cells can be shared with less resistant cells, possibly illuminating new ways to improve cancer treatments. The research was published June 29 in the journal Nature Communications.

“Cancer cells are often thought of as maverick cells that break the rules and, by doing so, end up damaging or even killing their host,” said Fred Adler, a professor of biology and mathematics who heads the U School of Biological Sciences. “But cancer cells in fact continue to depend on other cells in their environment to survive, particularly under the intense stress we place them under with drug treatment.”

Breast cancer is the most common cancer globally and the second-leading cause of cancer death in American women.

Adler helped lead an interdisciplinary research team, including oncologists from the Beckman Research Institute in Duarte, California, that used complex mathematical modeling to explore interactions between estrogen receptor-positive breast cancer cell lineages that are sensitive and resistant to the chemotherapy drug ribociclib. This drug is a kinase inhibitor that blocks the action of an abnormal protein that signals cancer cells to multiply, potentially impeding the spread of cancer cells.

Fred Adler

While cancer treatment has been successful in the short term with modern drugs that fight cancer with fewer side effects, long-term success has proven elusive.

“Many patients have cancers that recur because some cancer cells evolve to develop resistance to treatment and can resume growth,” Adler said. “If we can encourage drug-sensitive cells to take advantage of resistant cells, we can achieve the dual goal of limiting the cancer and of maintaining drug sensitivity to enable long-term cancer control.”

In the most common type of breast cancer, treatments almost always target the estrogen pathways that promote growth. And while combinations with modern targeted therapies have proven effective in controlling some cancers, the researchers tested what happens when cells evolve resistance to this combination therapy.

“We find, as expected, that these cells are able to grow with combination therapy, unlike their inexperienced drug-sensitive cousins,” Adler said. “However, we were quite surprised that this resistance is shared with the sensitive cells through overproduction of estrogen, which enables growth in the presence of treatment. The sensitive cells turn around and ‘bite the hand that feeds them’ by outcompeting the resistance cells.”

Both positive and negative interactions between drug-sensitive and resistant cells can influence the effectiveness of treatment in breast cancer cell populations. Adler and his colleagues have found that the interplay of those interactions in populations that feature differences between cancer cells—both within a single tumor or between a primary (original) tumor and a secondary tumor—are especially determinative.

“In mono- and coculture,” reported the study, which was funded by the National Cancer Institute, “we find that sensitive cells grow and compete more effectively in the absence of treatment.”

During treatment with ribociclib, sensitive cells survive and proliferate better when grown together with resistant cells than when grown in monoculture, termed in ecology as “facilitation,” defined as when one species positively impacts the fitness of another.

Contributors to the paper, titled “Cell facilitation promotes growth and survival under drug pressure in breast cancer,” include the lead co-authors Rena Emond and Jason I. Griffiths of the Beckman Research Institute; former U student Rachel S. Sousa, now at the University of California, Irvine; and others. The study was overseen by Beckman’s Andrea Bild.