A genetic screen to identify genes compensating for Crm1 (Xpo1) inhibition.

Compensatory responses to medicines used for the treatment of cancer are found upon administration of genotoxic chemotherapies and also upon administration of targeted therapies. Nuclear transport, both import and export, is a central pathway of interest in cancer cells. We undertook a transcriptomic approach for discovery of genes compensating for inhibition of the central nuclear export receptor Crm1, representing a major cancer cell vulnerability. We report here identification of the nuclear import receptor Ipo13 and the nuclear export receptor Xpo6 as genes compensating for Crm1 inhibition or depletion, through pharmacologic blockade with selinexor or through depletion or loss by short hairpin (shRNA) depletion or by CRISPR/Cas9 gene deletion.