For a study, researchers sought to understand that cisplatin/etoposide chemotherapy (C/E) plus and minus radiotherapy has been used to treat SCLC for several decades. The ubiquitin-proteasome system is a therapeutic target for SCLC that has received little attention. TAK-243, a first-in-class small molecule E1 inhibitor against UBA1, was tested in the lab. TAK-243 was tested in 26 SCLC cell lines as monotherapy and in combination with C/E, the PARP inhibitor olaparib, and radiation using cell viability assays. Investigators examined the TAK-243 response with gene expression to identify candidate biomarkers. TAK-243 was tested alone and combined with olaparib or radiotherapy on SCLC patient-derived xenografts (PDX). TAK-243 monotherapy was effective in most SCLC cell lines (EC50 median 15.8 nmol/L; range 10.2 nmol/L–367.3 nmol/L). TAK-243 sensitivity was linked to genes involved in the cell cycle, DNA and chromatin organization, and DNA damage repair.

In contrast, resistance was linked to cellular respiration, translation, and neurodevelopment genes. These correlations were also found in SCLC PDXs. In vitro, TAK-243 synergized with C/E and olaparib insensitive and resistant SCLC cell lines. In an SCLC PDX resistant to both drugs individually, significant TAK-243–olaparib synergy was observed. In an SCLC PDX, TAK-243 radiosensitization was also observed. TAK-243 was effective in preclinical SCLC models. TAK-243 sensitivity and resistance were related to gene set enrichment. TAK-243 exhibits synergy in cell lines and PDXs when combined with genotoxic therapies. TAK-243 may be used as a single agent or in combination with other therapies to improve SCLC patient outcomes.