Cancer cells’ ability to generate resistance-conferring mutations during therapy could offer one explanation for poor results observed in trials testing targeted therapies in glioblastoma, for instance, suggested Dr Draaisma. “It’s a possible explanation why these tumors don’t react to these targeted therapies.” That said, because glioblastomas typically form remarkably heterogenous tumors that consist of many different clones, it’s hard to rule out that resistance stems from clones with preexisting mutations, he explained.

Whether adaptive mutability could play a role in tumor resistance to nontargeted therapies, such as chemotherapy, is unclear. However, Dr Draaisma considered that possibility unlikely, due to observations made in a recent study.

He and his colleagues recently completed a study in 186 glioblastoma patients, comparing tumor samples before and after chemoradiotherapy with temozolomide.2 They found that at the whole-tumor level, the number of mutations in glioma-driving genes remained stable after treatment — a pattern very different from the genome-wide boost in mutations Dr Russo observed in colorectal cancer cells under targeted therapy.

Although the team did detect an increase in mutations at the individual gene level in a tenth of the samples, these could be largely explained by chemotherapy-induced genetic damage to particular DNA repair genes, Dr Draaisma explained.


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Interestingly, when Dr Russo and her colleagues exposed colorectal cancer cells to the chemotherapy drug oxaliplatin, the cells responded by increasing the production of DNA repair proteins, in contrast to the downregulation of those proteins in cells exposed only to targeted therapies. Cancer cells perhaps activate very different survival pathways depending on the type of therapy administered, she explained.

“The takeaway is that tumors really change under different types of stressful conditions, and therapies represent a strong stressful condition for the tumor, which always tries to survive,” Dr Russo said. More research is needed on how tumors adapt throughout the course of different therapies, she acknowledged. But, she added: “[What] would be really important is to be able to monitor the tumor constantly.”

References

  1. Russo M, Crisafulli G, Sogari A, et al.  Adaptive mutability of colorectal cancers in response to targeted therapies [published December 20, 2019]. Science. doi: 10.1126/science.aav4474
  2. Draaisma K, Chatzipli A, Taphoorn M, et al. Molecular evolution of IDH wild-type glioblastomas treated with standard of care affects survival and design of precision medicine trials: A report from the EORTC 1542 Study [published online November 19, 2019]. J Clin Oncol. doi: 10.1200/JCO.19.00367