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Colorectal Cancers Dial up Mutability in Response to Targeted Treatments

NEW YORK – A new study spelling out the range of mutations that can arise in colorectal cancer (CRC) in response to targeted treatments suggests that the tumors increase their mutation rate to become resistant.

As they reported online today in Science, researchers in Italy and the US tracked microsatellite stability, gene expression, and other molecular features in CRC lines treated with the EGFR inhibitor cetuximab (Erbitux from Eli Lilly) or the BRAF inhibitor dabrafenib (Novartis' Tafinlar).

Their results revealed resistant CRC cells with higher-than-usual levels of error-prone polymerase enzyme activity and increased microsatellite instability, along with reduced activity of DNA repair processes, including the mismatch repair (MMR) and homologous recombination (HR) repair pathways.

In a series of follow-up experiments, the team saw a similar shift — including a dip in MMR protein activity — in patient-derived xenograft models or tumor samples that were subjected to targeted therapy.

"The knowledge that cancer cells under therapeutic stress downregulate key effectors of the DNA repair machinery, such as MMR and HR, exposes a vulnerability that could be clinically exploited," senior and co-corresponding author Alberto Bardelli, an oncology researcher affiliated with the Candiolo Cancer Institute and the University of Torino, and his colleagues wrote.

"For example," they added, "it will be important to assess whether downregulation of HR proteins confers sensitivity to poly-ADP-ribose polymerases (PARP) inhibitors as observed in HR-deficient cancers."

In contrast to the notion that drug resistance strictly reflects the expansion of existing cancer sub-clones, the team suspected that targeted treatment resistance might arise through the advent of new alterations in the tumors — similar to the mutations that microbes acquire to dodge antibiotics.

"Bacterial persister cells can survive lethal stress conditions imposed by antibiotics through a reduction in growth rate," the authors explained. "A subsequent reduction in the efficiency of DNA mismatch repair (MMR), and a shift to error-prone DNA polymerases increases the rate at which adaptive mutations occur in the surviving population. Selection then allows the growth of mutant sub-populations capable of replicating under stressful conditions."

To search for similar examples of "de novo mutagenesis" in human cancers, the researchers first focused on CRC cell lines with wild-type BRAF and RAS genes or with BRAF V600E mutations. Although these cell lines were initially sensitive to drugs that targeted EGFR or BRAF, they explained, "a small number of drug-tolerant persister cells survived several weeks after treatment initiation."

Those resistance-related phenotypes appeared to be transient, the team reported, but became prevalent after long-term exposure to the targeted treatments. The drug sensitivity shifts were accompanied by diminished expression of genes from MMR and HR pathways, along with altered expression of a gene related to double-strand DNA break repair that codes for an exonuclease enzyme.

"We found that persister (drug-tolerant) cancer cells that survive EGFR and/or BRAF inhibition exhibit DNA damage, downregulate mismatch and homologous recombination repair proteins, switch from high-fidelity to error-prone DNA repair, and transiently increase their mutagenic ability," the researchers report.

The researchers confirmed their findings with additional DNA repair and HR assays, along with profiling on still other CRC cell lines. The patterns detected there also appeared to hold in half a dozen patient-derived xenograft models of CRC assessed using immunohistochemistry and in two clinical samples. 

Through a series of follow-up experiments, the authors documented a shift to error-prone DNA polymerase activity and a related rise in DNA damage and adaptive mutability in CRCs exposed to targeted treatments. Together, these and other results suggested that "cancer cells treated with targeted therapies activate stress-induced mutagenic mechanisms."