Some lung cancers are caused by an EGFR anomaly that drives cell multiplication. Targeted therapies like erlotinib effectively block this anomaly, yet the disease can recur. A new study in Science Advances reveals that surviving tumor cells accumulate DNA damage and acquire mutations that confer durable resistance.
At the start of treatment, a small fraction of cancer cells enter a state of 'drug tolerance,' surviving without multiplying. After some time, certain cells resume growth. Researchers replicated this phenomenon in lung cancer cells treated with erlotinib.
The enzyme TDP1, responsible for repairing DNA damaged by TOP1 complexes, plays a crucial role. During the tolerance phase, TDP1 and other TOP1cc repair proteins temporarily decrease in activity. Simultaneously, treatment increases oxidative stress, generating more TOP1ccs that accumulate on DNA, creating potentially mutagenic lesions.
This TOP1cc accumulation promotes the emergence of resistance-associated mutations, such as the EGFR T790M mutation, particularly when TDP1 is absent. Furthermore, TDP1-deficient cells proliferate more rapidly under prolonged treatment. Neutralizing oxidative stress with an antioxidant slows this proliferation, supporting a mechanism combining oxidative stress and DNA repair deficiency.
Researchers explored exploiting this fragility. By combining topotecan, a drug that increases TOP1ccs, with EGFR inhibition, TDP1-deficient tumor cells die. This cellular weakness could thus be transformed into a therapeutic leverage.
This vulnerability was observed in human tumors: out of 83 biopsies from non-small cell lung cancers with EGFR anomaly, 21 showed no detectable TDP1, approximately one-quarter of the patients studied. This suggests that a TDP1 measurement test could identify at-risk patients.
While promising, this discovery still requires validation in animal models and other cancer types and targeted treatments. The goal is to prevent resistance by better understanding the 'tolerance' window during which cancer cells become vulnerable to mutations.
