XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer

A multi-genomic approach identifies the addiction of KRAS -mutant lung cancer cells to XPO1-dependent nuclear export, offering a new therapeutic opportunity. Druggable targets in KRAS-driven tumours These authors use RNA interference screening of more than a hundred human non-small-cell lung cancer cell lines to identify phenotypic variations selectively required for the survival of cells carrying mutations in the KRAS gene. They find that KRAS-driven cancers are dependent on the nuclear export machinery. This vulnerability can be exploited by clinically available drugs targeting nuclear export receptor XPO-1, which inhibit tumour growth at least in part by promoting nuclear accumulation of NF-κB inhibitors. Conversely, some KRAS-driven tumours bypass this dependence through co-occurring mutations that result in YAP1 activation. This resistance mechanism can be countered by coadministration of the YAP1/TEAD inhibitor verteporfin. The common participation of oncogenic KRAS proteins in many of the most lethal human cancers, together with the ease of detecting somatic KRAS mutant alleles in patient samples, has spurred persistent and intensive efforts to develop drugs that inhibit KRAS activity 1 . However, advances have been hindered by the pervasive inter- and intra-lineage diversity in the targetable mechanisms that underlie KRAS-driven cancers, limited pharmacological accessibility of many candidate synthetic-lethal interactions and the swift emergence of unanticipated resistance mechanisms to otherwise effective targeted therapies. Here we demonstrate the acute and specific cell-autonomous addiction of KRAS -mutant non-small-cell lung cancer cells to receptor-dependent nuclear export. A multi-genomic, data-driven approach, utilizing 106 human non-small-cell lung cancer cell lines, was used to interrogate 4,725 biological processes with 39,760 short interfering RNA pools for those selectively required for the survival of KRAS -mutant cells that harbour a broad spectrum of phenotypic variation. Nuclear transport machinery was the sole process-level discriminator of statistical significance. Chemical perturbation of the nuclear export receptor XPO1 (also known as CRM1), with a clinically available drug, revealed a robust synthetic-lethal interaction with native or engineered oncogenic KRAS both in vitro and in vivo . The primary mechanism underpinning XPO1 inhibitor sensitivity was intolerance to the accumulation of nuclear IκBα (also known as NFKBIA), with