Not individual genes, but “mutation signatures” of many genes hold the key to better cancer therapies

Barcelona, ​​May 26, 2022,- Cancer therapy increasingly relies on a personalized approach, where genetic changes in an individual tumor can be used to determine the best therapeutic strategy. So far, in many cases, these genetic changes contain a so-called “driver mutation” that is said to predict the response to a drug. For example, mutations in the BRAF gene in melanoma predict response to BRAF inhibitory drugs, and amplifications in the ERBB2 gene in breast cancer predict response to ERBB inhibitory drugs.

However, these examples of successful drug markers are still quite rare. For many mutated driver genes, no specific drugs are available to address them. In addition, tumors from different patients show high variability in drug response and such variability is often not linked to mutations in the driver gene.

Researchers from IRB Barcelona, ​​led by Dr. Fran Supek, ICREA investigator and head of the Genome Data Science lab, have found that so-called “mutation signatures” can accurately predict the activity of various drugs applied to cancer cells derived from many types of tumors. These “mutation signatures” do not come from driver genes; instead, they reflect a collection of mutations found throughout a tumor’s genome. For example, the mutational signatures may reflect that the tumor has difficulty copying or repairing DNA, making it more amenable to therapy.

“We performed statistical analyzes using machine learning methods, jointly looking at the genome of cancer cells, their response to various drugs and their response to gene editing experiments. Surprisingly, our analysis revealed that the ‘classic’ genetic markers such as driver gene mutations or copy number changes are often less potent than the mutation signature genetic markers in predicting drug response,” explains Dr. Supek.

Different DNA repair deficiencies make cancer cells easier to target by many drugs

This study found many statistical predictions linking an observed mutational signature to the response (or lack of) to a cancer drug. It was previously known that a certain type of deficiency in so-called BRCA genes — which can cause breast, ovarian and prostate cancer — predicts response to drugs targeting BRCA deficiency. This deficiency also leaves a mutational signature in the genome of certain types of deletions (deleted DNA), which may indicate that the tumor is treatable with drugs that target BRCA deficiency.

In the current study, IRB Barcelona researchers, led by Marie Curie postdoctoral researcher Dr. Jurica Levatić, now a postdoctoral researcher at the Jozef Stefan Institute in Slovenia, showed that this is just one example of many: different types of DNA repair deficiency, such as defects in the ‘genomic spell check’ (DNA mismatch repair), can predispose cancer cells to make for sensitivity to certain drugs. Since tumors have compromised DNA repair mechanisms, these predicted therapies would have a greater ability to kill cancer cells and spare healthy cells.

Prior exposure to mutagenic chemicals, including drugs, may confer resistance to cancer cells on future therapies

The statistical and machine learning analyzes in this work, conducted jointly by Marina Salvadores, a PhD student in the Genome Data Science lab, can link databases from previous experiments in which many drugs have been tested on cancer cells growing in vitro (in the lab). ). In addition, this study also integrated experimental data on “genediting”, using CRISPR to knock out different drug target genes in the same types of cancer cells. This approach allowed the researchers to link drug target genes to drug treatments, adding confidence to their key finding that mutational signatures predict drug activity in cancer.

Interestingly, the cancer cells bearing genomic “scars” (mutation signatures) from previous exposure to mutagenic chemicals tended to be resistant to various chemotherapeutic drugs. One possible explanation for this is based on the known mechanism by which brain cancer cells, for example, can switch off their DNA repair system during treatment with the mutagenic drug TMZ, permanently turning them into strong, hypermutant cells that are resistant to a range of future treatments.

The study suggests that this type of adaptation is common in cancer. This has potential implications, as tumors caused by exposure to mutagens, e.g. exposure of the lungs to tobacco or exposure of the skin to UV light, may be more difficult to treat as the cells may have a long-lasting “memory” on dealing with DNA damage.

The algorithms used to identify the mutation signatures and link them to vulnerabilities in drugs are open access. Future work from the lab will focus on testing these prediction algorithms on patient data, overcoming the challenge of the scarcity of public genomic data for patients that correlate with randomized clinical trials.

This work has been funded by the EU through the ERC start-up grant “HYPER-INSIGHT”, the Horizon 2020 RIA project “DECIDER” and the Spanish Ministry of Science and Innovation.

/public release. This material from the original organisation/author(s) may be of a point in time, edited for clarity, style and length. The views and opinions are those of the author(s). View full here

#individual #genes #mutation #signatures #genes #hold #key #cancer #therapies

Leave a Comment

Your email address will not be published. Required fields are marked *