How Tumor Cells Evade Treatment by Playing Dead

A new study in Cancer Discovery explores how neuroblastoma cells survive treatment by entering a dormant state. The research, conducted by teams at the Experimental and Clinical Research Center (ECRC) in Berlin and other institutions, finds that the location of the MYCN oncogene determines whether tumor cells respond to chemotherapy or enter a state of dormancy.

Neuroblastoma, a cancer that affects the peripheral nervous system, occurs most often in children under five. In around 50% of cases, tumors regress without therapy. However, in the remaining cases, they grow rapidly and are initially responsive to chemotherapy. Most of these tumors later recur, typically within two years of treatment. Aggressive forms often show elevated numbers of MYCN gene copies.

Extrachromosomal DNA linked to dormancy

The study reports that MYCN is often found on extrachromosomal DNA (ecDNA), rather than within chromosomes. This location enables tumor cells to evade treatment. The researchers found that when MYCN is located on ecDNA, cells are more likely to enter a dormant, chemotherapy-resistant state.

This heterogeneity is caused by uneven distribution of ecDNA during cell division, which leads to tumor populations composed of both highly proliferative and dormant cells. The dormant cells, while not eliminated by chemotherapy, can later reawaken and contribute to cancer relapse.

Mouse models support dual-drug strategy

In experiments with tumor cell cultures, mouse models, and patient-derived samples, the researchers isolated and characterized subpopulations of neuroblastoma cells based on MYCN copy number. Cells with high MYCN levels were susceptible to chemotherapy, while cells with lower levels survived by entering a dormant state.

To address this challenge, the team tested a combination therapy in mice. Alongside standard chemotherapy, they administered a second compound that targets senescent or dormant cells. This two-pronged approach showed improved outcomes, reducing the number of cells capable of reinitiating tumor growth.

Targeting ecDNA-driven cancers

The proposed strategy may be limited to cancers in which oncogenes are located on ecDNA. For tumors with chromosomally integrated oncogenes, different approaches would be needed.

The researchers aim to expand the search for compounds that selectively target dormant tumor cells in human tissue without harming healthy cells. They also note that similar ecDNA-driven mechanisms could play a role in other aggressive cancers, including certain brain tumors.

Reference: Montuori G, Tu F, Qin D, et al. Extrachromosomal DNA-driven oncogene dosage heterogeneity promotes rapid adaptation to therapy in MYCN-amplified cancers. Cancer Discov. 2025. doi: 10.1158/2159-8290.CD-24-1738

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