In vivo assessment of differential toxicity of cancer treatment drugs in Fanconi Anemia

Abstract

Fanconis Anemia (FA) is a DNA repair disorder with a very elevated risk of cancer, especially squamous cell carcinomas (SCC). Many cancer chemotherapy agents induce DNA damage, are highly toxic in FA, and cannot be safely used in this population. The potential differential toxicity to FA patients of many new drugs being explored for use in SCC is unknown. To evaluate such compounds of unknown toxicity for use in FA cancers, we developed a sensitive in vivo bone marrow repopulation competition assay in mice. We found that afatinib, alisertib and everolimus exhibited no significant differential toxicity in this system. Therefore, these drugs are candidates for chemotherapy of cancers in human FA patients. Our competitive repopulation assay provides a robust method to screen novel chemotherapy agents for their safety in FA. Summary- We developed a mouse model system for evaluating differential toxicity of cancer chemotherapy drugs on Fanconi Anemia mutant hematopoietic cells in vivo. - Different drugs resulted in either increases, decreases, or neutral wildtype to Fanconi mutant cell ratios permitting robust assessment of their safety in FA.