Enhanced phosphorylation of c-Jun by cisplatin treatment as a potential predictive biomarker for cisplatin response in combination with patient-derived tumor organoids.

Despite recent advancement in sequencing technologies and large-scale drug screenings with hundreds of cell lines, the predictive accuracy of mutation-based biomarkers is still insufficient to guide cancer therapy. Therefore, novel types of diagnostic methods with alternative biomarkers are highly appreciated. To develop the novel methods, we hypothesized that sensitivity-specific changes in phosphorylations of signaling molecules could be useful as predictive biomarkers. Here, we aimed to develop predictive methods for cisplatin with a combination of such type of biomarker(s) and patient-derived tumor organoids (PDOs). We found that cisplatin sensitive cell lines or PDOs showed enhanced phosphorylation of c-Jun (p-c-Jun) within 24 h in response to cisplatin treatment. We also compared responses to cisplatin in 6 PDOs with therapeutic effect of neoadjuvant chemotherapy (docetaxel/cisplatin/5-fluorouracil) in 6 matched patients. Mechanistically, the c-Jun induction was partly related to TNF signaling induced by cisplatin. Thus, our data implicates the feasibility of enhanced p-c-Jun by cisplatin treatment as a predictive biomarker for the efficacy. To identify genes that are regulated by JNK/c-Jun after a cisplatin treatment, we explored global gene expression profile after 24 h cisplatin treatment with or without JNK inhibitor (SP600125) for the last 3h of the treatment.