Abstract: The invention relates to the co-administration of select proteasome and PI3K inhibitors is useful for treating c-Myc-overexpressing cancers, particularly hematological cancers such as aggressive B- and T-cell lymphomas. In exemplified embodiments, coadministration of a dual PI3K/CK-1 inhibitor with a proteasome inhibitor synergistically increases cell death of aggressive B- and T-cell lymphomas as well as multiple myeloma over the individual or additive effect of either or both agents. This synergistic effect is associated with the previously unknown inhibition of the kinase casein kinase 1 epsilon (CK-1?) by a PI3K inhibitor, such as TGR-1202. Accordingly, use of PI3K inhibitors that possess CK-1? inhibition in combination with proteasome inhibitors provides a new therapy regime for treating c-Myc-overexpressing cancers, and particularly hematological cancers.