Under exposure to antibiotics, many bacteria respond by boosting the number of mutations in their genomes, doing so by limiting DNA repair mechanisms and increasing the expression of error-prone DNA replication enzymes. This strategy, known as adaptive mutability, affords them a better chance of creating a resistance-conferring mutation that will protect them against the antibiotic in question.

Recently, a team of American and European scientists reported that human colorectal cancer cells appear to share this ability, harnessing this feature to survive treatment with targeted therapies — offering an explanation for how cancers can recur. The results were published in Science in December 2019.1

It has long been assumed that when secondary resistance occurs during targeted therapy, it is due to the proliferation of preexisting cancer cells that harbor resistance-conferring mutations. The new findings suggest that de novo mutations can also arise, during therapy itself.

“What they found is very interesting — that the tumor is fairly flexible and evolves over time, through up- and downregulation of certain pathways, and they become more resistant to drugs,” Kaspar Draaisma, MD, Erasmus University Medical Center, Rotterdam, the Netherlands and the University of Liège, Belgium, who wasn’t involved the research, told Cancer Therapy Advisor.


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The authors had conducted a series of experiments with human colorectal cancer cells, which they exposed to targeted therapies such as cetuximab, an epidermal growth factor receptor (EGFR)-targeting drug approved for use in certain patients with metastatic colorectal cancer whose tumors lack RAS mutations.

Transcriptional profiling of survivor cells that persisted under the therapy revealed that the use of the drug downregulates the expression of DNA repair proteins — those encoded by mismatch repair (MMR) genes—while upregulating expression of error-prone DNA replication enzymes.

Similar results were also detected in an analysis of patient-derived tissue grafted into mice, as well as in colorectal tumor samples. Together with other analyses that indicated an increased mutation rate in cells exposed to the drugs, the data suggested that cancer cells, just like bacteria, increase their mutation rate to survive in the face of therapeutic pressure, the authors concluded.

To Mariangela Russo, PhD, an assistant professor at the University of Turin’s department of oncology at Italy’s Candiolo Cancer Institute, and first author of the study, the finding that resistance-conferring mutations could be acquired during therapy and aren’t necessarily preexistent in primary tumors, offers a new avenue for developing targeted therapies.

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Metastatic colorectal cancers frequently develop resistance to targeted therapies. While some researchers are working toward finding new drug targets to counteract certain mutations, Dr Russo suggested another approach: to identify and target the pathways the cells use to enhance their mutability. “That’s what we hope would delay the onset of resistance,” she said.

The capacity for adaptive mutability likely extends beyond colorectal cancer, Dr Russo added. “It’s something that we are trying to test now in the laboratory — to verify whether this occurs in other [cancer] tissues such as lung, melanoma, pancreas; many other types of cancer that are usually treated with targeted therapies.”