Most children with acute lymphoblastic leukemia (ALL) can be cured, but the prognosis is dismal for about 20% of patients who relapse after treatment.

Now, a new study from researchers at Columbia University’s Herbert Irving Comprehensive Cancer Center has found that a mutation that leads to relapse in many ALL patients also causes a weakness that could be exploited to kill the cancer cells in patients experiencing relapse.

The research, led by Adolfo Ferrando, MD, PhD, found that mutations in a gene called NT5C2 make leukemic cells resistant to a common chemotherapy treatment, but vulnerable to a class of drugs called IMPDH inhibitors.

“Increased sensitivity to IMPDH inhibition shows proof of principle that the pathway for resistance provides a new therapeutic target,” Dr. Ferrando says. “IMPDH inhibitors could eventually emerge as relevant anti-leukemic drugs, but this would require additional preclinical work before clinical testing.”

NT5C2 mutation emerges during remission

Cancer cells are like moving targets, genetically changing to thrive and multiply. They evolve ways to survive the onslaught of treatment, so patients often stop responding to a particular drug.

Dr. Ferrando’s lab had previously found that cancer cells from relapsed ALL patients frequently have a mutation in a gene called NT5C2 and that these mutations drive resistance to a common chemotherapy treatment, 6-mercaptopurine.

How this mutation emerges as cancer recurs after remission was unclear until now. Using samples from patients in remission, the researchers detected the NT5C2 mutation in cancer cells before patients were clinically diagnosed as relapsed. However, the mutation was not detectable in most cases at the time of diagnosis.

What do these findings mean for ALL patients?

The findings suggest that cells with the NT5C2 mutation only multiply in response to treatment, and doctors can be on the lookout for the mutation as an indicator of a patient’s potential to relapse. “This seems to be a late mutation involved in disease progression. Our data support that it may not be present at diagnosis in many cases, and that in cases where it may be present, it represents a very minor population,” says Dr. Ferrando.

The study also paves the way for the discovery of new treatment options. “In this case, by understanding the mechanisms of resistance, we are now positioned to design new strategies to curtail the occurrence of relapse,” says Dr. Ferrando.