Plain language summary: Enhancing transcription–replication conflict targets ecDNA-positive cancers
Below is a plain language summary of Enhancing transcription–replication conflict targets ecDNA-positive cancers, a paper published in Nature in November 2024 by Cancer Grand Challenges team eDyNAmiC.
It has been co-developed by the team eDyNAmiC patient advocates. It was written by Shirin Khalili, Katell Maguet, Dave Chuter, and Andrew Lang, based on first draft versions written by the first authors of the paper.
A key molecular “traffic officer” is overworked in ecDNA(+) cancer cells and creates a therapeutic vulnerability
Background information: Transcription is a process by which a temporary copy of a gene is made; it occurs in all living cells. Before a cell can divide into two new cells, it must create a new copy of its existing DNA: this is called DNA replication. Both machineries work on the same piece of DNA.
Extrachromosomal DNA (ecDNA) is a small circular DNA molecule that poses a major challenge for cancer treatment because it has a unique biology. ecDNA enables cancer cells to turbo-charge the machinery that drives their growth and ability to become resistant to treatment. Patients with ecDNA(+) cancers have worse outcomes than patients with ecDNA-negative cancers. To develop more effective therapies for patients with ecDNA(+) cancers, we need to find out if there is a way to target that unique biology.
The high level of transcription from ecDNA is generally considered to be advantageous for a tumor because this means the cells can produce far more pro-cancer proteins that make cells grow and multiply faster. But all this extra transcription turns ecDNA into a messy construction site causing a molecular traffic jam and makes it more difficult to finish DNA replication accurately, which damages the ecDNA molecules. Because of this traffic jam, ecDNA(+) cells strongly depend on an overworked traffic officer (CHK1 protein) to help the cells cope with this stress. Certain drugs can interfere with the ability of CHK1 to do its job, which would cause the ecDNA(+) cancer cell to self-destruct.
This study demonstrates the above and presents a novel, highly specific, potent, oral drug (BBI-2779) that interferes with CHK1’s ability to do its job and preferentially kills ecDNA(+) tumor cells. To show that it works beyond the lab, this novel drug was tested in mice with ecDNA(+) stomach cancer. BBI-2779 suppressed tumor growth and prevented the tumor from gaining resistance to the cancer drug infigratinib, resulting in strong and continuous tumor shrinkage in these mice. This work demonstrates the feasibility of using a synthetic molecule to turn the otherwise advantageous ecDNA biology against itself and potentially change a terrible prognosis to a treatable one.
