New Technique Fights Mutant Cancer Cells By Making More Mutations

Researchers are devising ways to paint targets on cancer cells. Drugs that unleash the immune system against cancer can be effective, but they appear to work best on the subset of tumors that are most riddled with mutations.

Photo Insert: An illustration of cancer cells

Enter a controversial solution: use chemotherapy to deliberately create new mutations in tumors and thus make them more vulnerable to an immune system attack, Jocelyn Kaiser reported for Science. Lab studies and several small clinical trials already hint the strategy may help.

“There might be an opportunity to begin to remodel the genetics of the tumor in such a way” that immunotherapy works better, a leader of one trial, cancer geneticist Luis Diaz of Memorial Sloan Kettering Cancer Center, said at a plenary session here at the annual meeting of the American Association for Cancer Research (AACR).

Still, some cancer researchers are leery of purposely inducing mutations and say animal experiments suggest doing so could cause more harm than good.

“I question the rationale,” says melanoma immunotherapy researcher Antoni Ribas of the University of California, Los Angeles (UCLA.) Drugs called checkpoint inhibitors remove a molecular brake that keeps immune sentries called T cells from attacking tumors.

They work best on cancers such as lung tumors triggered by smoking-induced DNA damage and melanomas, which accumulate mutations from ultraviolet (UV) light. Many of these genetic changes cause cells to make “neoantigens,” novel protein fragments on tumor cells that flag them to T cells.

The notion that forcing cancer cells to make more neoantigens might bolster immunotherapy traces back to studies of tumors with defects in certain mechanisms that repair DNA.

These cancer cells accumulate many mutations, and in 2015 a team led by Diaz, then at Johns Hopkins University, reported that checkpoint drugs work well on multiple tumor types with these “mismatch” DNA repair defects.

Cancer geneticist Alberto Bardelli of the University of Turino and colleagues went further by deliberately inactivating a mismatch repair gene in tumor-bearing mice. They reported in Nature in 2017 that the change resulted in a buildup of DNA errors in the cancer cells and boosted the effectiveness of checkpoint drugs.

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