The main obstacles that lead to clinical failure in cancer treatment are the development of resistance to chemotherapy and a rise in invasive characteristics in cancer tumor cells due to prolonged chemotherapeutic processes. A new mouse study reveals that low doses of a four-drug combination help prevent the spread of cancer without triggering drug resistance or recurrence by simultaneously targeting multiple pathways within a metastasis-promoting network.

The findings are published in the journal eLife in a paper titled, “Limited inhibition of multiple nodes in a driver network blocks metastasis,” and led by researchers at the University of Chicago, the University of São Paulo in Brazil, the University of North Carolina, and the University of Texas Southwestern Medical Center.

“Metastasis suppression by high-dose, multi-drug targeting is unsuccessful due to network heterogeneity and compensatory network activation,” wrote the researchers. “Here we show that targeting driver network signaling capacity by limited inhibition of core pathways is a more effective anti-metastatic strategy.”

Current approaches to treating metastatic cancer have focused on high doses of individual drugs or drug combinations to hinder pathways that promote the spread of cancer cells. However, the approaches can be toxic to the patient and may activate other pathways that cause the drugs to stop working.

“There is an urgent need for new strategies to suppress cancer metastasis, especially for cancers such as triple-negative breast cancer that currently lack effective therapies,” asserted Ali Yesilkanal, PhD, first author of the study and a postdoctoral scholar at the Ben May department for cancer research at the University of Chicago.

The researchers analyzed gene expression data from patients participating in the Cancer Genome Atlas study to understand how a metastasis-suppressing protein called Raf Kinase Inhibitory Protein (RKIP) works.

“This principle underlies the action of a physiological metastasis suppressor, Raf Kinase Inhibitory Protein, that moderately decreases stress-regulated MAP kinase network activity, reducing output to transcription factors such as pro-metastastic BACH1 and motility-related target genes,” noted the researchers.

The researchers developed a low-dose four-drug combination that mimics how RKIP suppresses the cancer cells’ ability to spread. They observed that the treatment blocked metastatic colonization in mouse breast cancer models and increased survival. The treatment also did not trigger the compensatory mechanisms that often cause high-dose, anti-metastasis drugs to stop working and tumors to return.

The team of researchers then used computer modeling to explain why reducing, but not completely stopping, the expression of this network of genes helped prevent metastasis without triggering drug resistance or relapse.

“Our findings could lead to a new cancer treatment strategy where patients first receive low-dose combination drugs that block metastasis and then receive traditional cancer treatments such as radiation, chemotherapy, or immunotherapy,” added co-senior author Marsha Rosner, the Charles B. Huggins professor at the Ben May department of cancer research at the University of Chicago.

“Our results challenge current approaches to cancer treatment and suggest an alternative strategy for controlling metastasis in breast cancer and potentially other types of cancer,” concluded co-senior author Alexandre Ramos, group leader at the School of Arts, Sciences and Humanities, University of São Paulo, Brazil.

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