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

Abstract

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 activity1. 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 consequent inhibition of NFκB transcription factor activity. Intrinsic resistance associated with concurrent FSTL5 mutations was detected and determined to be a consequence of YAP1 activation via a previously unappreciated FSTL5–Hippo pathway regulatory axis. This occurs in approximately 17% of KRAS-mutant lung cancers, and can be overcome with the co-administration of a YAP1–TEAD inhibitor. These findings indicate that clinically available XPO1 inhibitors are a promising therapeutic strategy for a considerable cohort of patients with lung cancer when coupled to genomics-guided patient selection and observation.

Therapeutic Effects of XPO1 Inhibition in Thymic Epithelial Tumors

“…While loss of p53 activity can cause resistance to the XPO1 inhibitor under certain circumstances, other alterations such as XPO1 amplification may also contribute to the resistance. Our conclusions are also supported by other studies that indicated that in certain tumors, expression of certain TSPs is needed for selinexor sensitivity, whereas in other tumors, inactivation of these TSPs does not affect drug sensitivity (18,(31)(32)(33)(34).…”

“…Although not functionally examined in this study, inhibition of NF-kB by selinexor likely plays a role in the selinexor-induced cytotoxicity in TETs as well. Recently, it was shown that a synthetic-lethal interaction of XPO1 inhibition with KRAS mutation in NSCLC cells requires its inhibition of NF-kB transcription factor activity (34).…”

Effect of miR-21 on Apoptosis in Lung Cancer Cell Through Inhibiting the PI3K/ Akt/NF-κB Signaling Pathway in Vitro and in Vivo

“…Consistently, LY obviously down-regulated the apoptotic proteins induced by the miR-21 inhibitor. A previous study demonstrated that XPO1 inhibitor sensitivity to lung cancer was involved in the inhibition of NF-κB transcription factor activity [37]. Kashyap et al indicated that Selinexor showed significant anticancer activity against osteosarcoma by NF-kB inhibition [38].…”

Inhibition of nucleo-cytoplasmic shuttling through XPO1/CRM1: A unique therapeutic approach for treatment of haematological and solid malignancies

“…Additionally, XPO1 inhibitors (KPT-185 and KPT-330) verified that IC50 value for KRAS-mutant cell lines was significantly lower than KRAS-wild type cells. Further, XPO1 inhibitor selinexor (KPT-330) confirmed greater selectivity and anti-tumor activity towards KRAS-mutant in xenograft murine models (KRAS-wild-type and KRAS-mutant NSCLC cells), patient-derived xenograft model with KRASG12D and genetically engineered mouse (KrasLSL-G12D, p53fl/fl) [68] . Selinexor treatment showed stable disease in patients with KRAS-mutation (44%) versus the patients with wild-type KRAS in phase-I clinical trials in colon cancer [69] .…”

“…Another report also confirmed that XPO1 inhibitors (KPT-185 and KPT-276) have an anti-cancer effect in NSCLC preclinical models [67] . Most recently, nuclear export receptor XPO1 has been identified as a druggable target in KRAS-mutant NSCLC using short interfering RNA screening [68] . Silencing of XPO1 showed a marked decrease in the viability of KRAS-mutant cells.…”