Fig. 8: Proposed mechanism of action of ataluren and amlexanox.

While both ataluren and amlexanox should induce translational read-through (and thus reduce the DNA damage repair deficiency, which would also result in reduced p53 levels), amlexanox is not able to improve cell survival upon genotoxic stress. There is admittedly a partial effect on FANCA protein expression and p53 reduction, indicating a broader spectrum of action. In Fanconi Anemia, amlexanox may have a stronger effect downstream of the DNA damage by inhibiting TBK1/IKKε, as already described in the literature, thus reducing the throughput of the IRF3/IFN-I and STAT2 pathway as well as NF-κB activation. Of note, according to ENCODE data, TP53 is a target gene of IRF3 transcription factor: this could be the main cause of the observed reduction in p53, which in this case does not translate into an overall improvement in cell fitness.