a-1331852 and selinexor

XPO1 (exportin1) mediates nuclear export of proteins and RNAs and is frequently overexpressed in cancers. In this study, we show that the orally bioavailable XPO1 inhibitor KPT-330 reduced Mcl-1 protein level, by which it synergized with Bcl-xL inhibitor A-1331852 to induce apoptosis in cancer cells. KPT-330/A-1331852 combination disrupted bindings of Mcl-1 and Bcl-xL to Bax, Bak, and/or Bim, elicited mitochondrial outer membrane permeabilization, and triggered apoptosis. KPT-330 generally mitigated mRNA expression and protein synthesis rather than mRNA nuclear export or protein stability of Mcl-1. KPT-330 inhibited mTORC1/4E-BP1 and Mnk1/eIF4E axes, which disrupted the eIF4F translation initiation complex but was dispensable for Mcl-1 reduction and KPT-330/A-1331852 combination-induced apoptosis. Mature rRNAs are integral components of the ribosome that determines protein synthesis ability. KPT-330 impeded nucleolar rRNA processing and reduced total levels of multiple mature rRNAs. Reconstitution of XPO1 by expressing degradation-resistant C528S mutant retained rRNA amount, Mcl-1 expression, and Bcl-xL inhibitor resistance upon KPT-330 treatment. KPT-330/A-1331852 combination suppressed growth and enhanced apoptosis of non-small cell lung cancer xenografts. Therefore, we clarify the reason of apoptosis resistance of cancer cells to XPO1 inhibition and develop a potential strategy for treating solid tumors.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzothiazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Down-Regulation; Drug Synergism; Eukaryotic Initiation Factor-4F; Exportin 1 Protein; Humans; Hydrazines; Isoquinolines; Karyopherins; Lung Neoplasms; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred NOD; Mice, SCID; Myeloid Cell Leukemia Sequence 1 Protein; Receptors, Cytoplasmic and Nuclear; RNA, Ribosomal; Triazoles