“…Our work expands upon prior studies suggesting a potential association between APOBEC-mediated mutagenesis and acquisition of putative resistance mutations in the APOBEC-preferred context during the treatment of EGFR-driven lung cancers 74,75 . Our data suggest that inhibition of APOBEC3 family members could suppress the emergence of one pathway to resistance and thereby improve response to targeted therapy, consistent with the work of others in the field that suggests that multiple APOBEC3 family members including A3B contribute to targeted therapy resistance 5,32 , with both A3A and A3B shown to be contributors of mutagenesis 6,32,36,76 . The role of A3B in promoting resistance to TKI is likely multifaceted, and our data do not discount the contribution of other possible parallel cytosine deaminase-independent mechanisms, such as induced CIN 4,77 , regulation of cell cycle 22 and regulation of the DNA damage repair pathway 78,79 .…”