Antitumor efficacy of XPO1 inhibitor Selinexor in KRAS-mutant lung adenocarcinoma patient-derived xenografts

• Published in: Translational oncology Vol. 14; no. 10; p. 101179
• Main Authors: Rosen, Joshua C., Weiss, Jessica, Pham, Nhu-An, Li, Quan, Martins-Filho, Sebastiao N., Wang, Yuhui, Tsao, Ming-Sound, Moghal, Nadeem
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2021; Neoplasia Press; Elsevier
• Subjects: KRAS; Lung adenocarcinoma; Original Research; Patient-derived xenografts; Targeted therapeutics; XPO1; Targeted therapeutics; KRAS; XPO1; Lung adenocarcinoma; Patient-derived xenografts
• ISSN: 1936-5233; 1936-5233
• DOI: 10.1016/j.tranon.2021.101179

•The XPO1 inhibitor Selinexor inhibits growth of KRASmut lung cancer PDXs.•Selinexor is effective in G12C and non-G12C KRASmut lung cancers.•Selinexor Is more effective than the MEK inhibitor trametinib in KRASmut lung cancers.•Selinexor is less effective than kinase inhibitors in kinase-driven lung cancers. Gain-of-function Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations occur in 25% of lung adenocarcinomas, and these tumors are challenging to treat. Some preclinical work, largely based on cell lines, suggested KRASmut lung cancers are especially dependent on the nuclear export protein exportin-1 (XPO1), while other work supports XPO1 being a broader cancer dependency. To investigate the sensitivity of KRASmut lung cancers to XPO1 inhibition in models that more closely match clinical tumors, we treated 10 independently established lung cancer patient-derived tumor xenografts (PDXs) with the clinical XPO1 inhibitor, Selinexor. Monotherapy with Selinexor reduced tumor growth in all KRASmut PDXs, which included 4 different codon mutations, and was more effective than the clinical MEK1/2 inhibitor, Trametinib. Selinexor was equally effective in KRASG12C and KRASG12D tumors, with TP53 mutations being a biomarker for a weaker drug response. By mining genome-wide dropout datasets, we identified XPO1 as a universal cancer cell dependency and confirmed this functionally in two KRASWT PDX models harboring kinase drivers. However, targeted kinase inhibitors were more effective than Selinexor in these models. Our findings support continued investigation of XPO1 inhibitors in KRASmut lung adenocarcinoma, regardless of the codon alteration.