Cancer cells often harbor extrachromosomal DNA (ecDNA) in circular structures, which scientists are now targeting for novel therapies. A Stanford Medicine-led team has uncovered how these DNA circles contribute to cancer development and drug resistance, revealing potential new therapeutic strategies.
The research, detailed in multiple papers published in Nature, demonstrates that ecDNAs can contain not only oncogenes and immune response modulators but also enhancer sequences that drive gene expression on other ecDNAs. This collaborative interaction between different types of ecDNAs is crucial for cancer cell growth, challenging conventional views of cancer genetics.
Collaborative ecDNA Activity
"The ecDNAs with enhancer elements don’t confer any benefit to the cell on their own; they have to work with other ecDNAs to spur cancer cell growth," explained Howard Chang, MD, PhD, professor of genetics at Stanford University. This teamwork and physical connection between different types of circles is actually very important in cancer development.
Inheritance of ecDNA
Further studies revealed that ecDNAs, unlike chromosomes, continue transcription during cell division. This leads to the segregation of interconnected multi-circle units to daughter cells, ensuring the inheritance of advantageous ecDNA combinations. This non-Mendelian inheritance pattern gives cancer cells a significant survival advantage.
"It’s like getting a good hand in poker. Cancer cells that get dealt that good hand over and over have a huge advantage. Now we understand how this happens," Chang noted.
Therapeutic Targeting of ecDNA
The team discovered that the high level of transcription in ecDNA-containing cells creates a vulnerability. Blocking the activity of the checkpoint protein CHK1 causes the death of these tumor cells and tumor regression in mice with gastric tumors fueled by ecDNAs.
"This turns the table on these cancer cells," Chang said. "They are addicted to this excess transcription; they can’t stop themselves. We made this into a vulnerability that results in their death."
Clinical Trials
The promising results have led to a CHK1 inhibitor entering early-phase clinical trials for patients with cancers that have multiple copies of oncogenes on ecDNAs. This therapeutic approach targets the unique vulnerabilities of cancer cells driven by ecDNA, offering a potential new treatment avenue.
"These papers represent what can happen when researchers from many different labs come together with a common goal," said Paul Mischel, MD, professor of pathology at Stanford University. "Science is a social endeavor and together, through many avenues of converging data from wildly different sources, we’ve shown that these findings are real and important."
