Landscape of synthetic lethal genes after APOBEC activation in lung cancer cells. Credit: Institute for Research in Biomedicine – IRB

In cancer, personalized medicine uses the unique genetic mutations of an individual tumor to find its weak points and to combat it. Many tumors have a higher number of mutations due to an antiviral defense mechanism called the APOBEC system, which can inadvertently damage DNA and cause mutations.

Researchers from the IRB Barcelona under the direction of Dr. Travis Stracker and Dr. Fran Supek found that the HMCES enzyme is the Achilles’ heel of some lung tumors, especially those with a higher number of mutations caused by the APOBEC system.

“We found that blocking HMCES is very harmful to cells with an activated APOBEC system (which are many lung cancer cells), but much less to those who are not activated (as is often the case with healthy ones Cells is the case). ” explains Dr. Supek, ICREA Researcher and Head of the Genomic Data Science Laboratory at IRB Barcelona.

“HMCES not only shows specificity for cancer cells, but it is also potentially suitable for drugs. This makes it an excellent candidate for future lung cancer treatments,” added Dr. Stracker, a former group leader at IRB Barcelona who is now at the National Cancer Institute (NIH / NCI) in the United States.

A multidisciplinary approach to reviewing the best strategy

The study involved the collaboration of two research groups working on different disciplines and included both a computational and an experimental approach. Genetic screening experiments were performed on different types of human pulmonary adenocarcinoma cell lines using CRISPR / Cas9. “These experiments can interrogate the effects of removing each gene from cancer cells individually and allow us to see whether the cancer can tolerate this change,” say Josep Biayna and Isabel Garcia Cao, researchers at IRB Barcelona and first and second authors of the article . Previous data from CRISPR gene screenings performed by other laboratories were also statistically analyzed and confirmed the experimental results.

A mutation nebula caused by a defense system

When cells detect a mismatch in their DNA, they go through a DNA repair reaction to obtain the genetic information. Remarkably, this reaction can be coupled to the APOBEC enzymes, which are typically used by human cells to fight viruses and play an important role in the fight against hepatitis and HIV. This mechanism was previously described by the Genome Data Science laboratory and indicates that in some cases, when the APOBEC enzymes and the DNA repair process are active at the same time, APOBEC hijacks the DNA repair and thus creates the mutation fog.

Outsmart cancer development

Late-stage cancers can accumulate large numbers of mutations in their DNA, which can make the cancer more aggressive or more drug-resistant. Many of these mutations can be caused by APOBEC, which accelerates tumor development. Therefore, killing cancer cells that activate APOBEC should slow tumor development and prevent new dangerous mutations from developing.

Scientists are discovering that normal DNA repair processes can become a major source of mutations in cancer

More information:
Josep Biayna et al. The loss of HMCES is synthetically lethal with APOBEC activity in cancer cells (2021). DOI: 10.1101 / 2021.02.05.429803 Provided by the Institute for Research in Biomedicine (IRB Barcelona)

Quote: Scientists identify a potential target for the treatment of lung cancer (2021 April 7), accessed April 7, 2021 from has been

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