Tyrosine kinases such as EGF are frequently dysregulated in cancer and signal downstream to multiple growth and survival pathways, including the RAS/RAF/MEK/ERK and the PI3K/AKT pathways. The prosurvival actions of these pathways are mediated, at least in part, through phosphorylation of proapoptotic and antiapoptotic BCL-2 family proteins (e.g., BIM, BAD, and MCL-1), leading to alterations in the relative abundance of as well as interactions between these proteins. Note that AKT acts indirectly to spare MCL-1 by inhibiting glycogen synthase kinase–mediated (GSK-mediated) MCL-1 phosphorylation and degradation. TKIs act by blocking EGF signaling to these key pathways, and modification of the balance between BCL-2 family proteins may contribute to TKI-mediated lethality. As shown by the dashed arrows, FAM83A and FAM83B could theoretically act downstream of EGF but upstream of BRAF and p85-PI3K to promote activation of these survival pathways, leading to attenuation of cell death. FAM83A and FAM83B may also, through a yet to be defined mechanism, modify the extent or tonicity of EGF signaling itself. By acting at sites downstream of EGF, FAM83A and FAM83B may thereby bypass the block to EFG survival signaling induced by TKIs, effectively relieving the cell of its addiction to this survival pathway. Such a phenomenon could theoretically be prevented by either developing inhibitors of FAM83A and/or FAM83B that interfere with their interactions with proteins such as BRAF or specifically targeting downstream components of the pathways responsible for the prosurvival actions of these proteins. Adapted with permission from Nature Reviews Cancer (17).