Lung cancers are highly resistant to radiotherapy, necessitating the use of high doses, which leads to radiation toxicities such as radiation pneumonitis and fibrosis. Caffeic Acid Phenethyl Ester (CAPE) has been suggested to have anti-proliferative and pro-apoptotic effects in tumour cells, while radioprotective anti-inflammatory and anti-oxidant effects in the normal tissue. We investigated the radiosensitizing and radioprotective effects of CAPE in lung cancer cell lines and normal tissue in vitro and ex vivo, respectively. The cytotoxic and radiosensitizing effects of CAPE in lung cancer were investigated using viability and clonogenic survival assays. The radioprotective effects of CAPE were assessed in vitro and ex vivo using precision cut lung slices (PCLS). Potential underlying molecular mechanisms of CAPE focusing on cell cycle, cell metabolism, mitochondrial function and pro-inflammatory markers were investigated. Treatment with CAPE decreased cell viability in a dose-dependent manner (IC₅₀ 57.6±16.6μM). Clonogenic survival assays showed significant radiosensitization by CAPE in lung adenocarcinoma lines (p<0.05), while no differences were found in non-adenocarcinoma lines (p≥0.13). Cell cycle analysis showed an increased S-phase (p<0.05) after incubation with CAPE in the majority of cell lines. Metabolic profiling showed that CAPE shifted cellular respiration towards glycolysis (p<0.01), together with mitochondrial membrane depolarization (p<0.01). CAPE induced a decrease in NF-κB activity in adenocarcinomas and decreased pro-inflammatory gene expression in PCLS. The combination of CAPE and radiotherapy may be a potentially effective approach to increase the therapeutic window in lung cancer patients.

Background: Previous studies mainly investigated singular serum tumor marker (STM) measurements for the management of advanced cancer patients, resulting in differences between recommended cut-off points and associated accuracies in evaluating treatment outcomes. We aimed to determine which STM dynamics recur during treatment in advanced non-small cell lung cancer (NSCLC) patients with disease control three months after starting with immune checkpoint inhibitor (ICI)-containing treatment and explore whether these dynamics retain information on treatment outcomes. Methods: This real-world exploratory multi-center observational cohort study included advanced NSCLC patients with clinical and radiological disease control three months after starting with ICI-containing treatment and at least three STM measurements for at least one STM during treatment. STM dynamics visualized for all patients were subclassified into three serological response patterns by two investigators who were blinded for treatment outcomes. Results: Between March 2013 and January 2023, 256 patients were included at two thoracic oncology outpatient clinics in The Netherlands. Kaplan–Meier survival analyses showed a significant association between the serological response patterns and both progression-free survival (PFS) and overall survival (OS). Additionally, the serological response patterns could be used to distinguish a durable response versus secondary treatment resistance, and oligoprogression versus systemic progression. Conclusions: Our findings underscore the value of monitoring STM dynamics in advanced NSCLC patients during ICI-containing treatment to improve response classification and decision-making in clinical practice. Future studies should explore the value of the identified dynamics in other tumor- and systemic treatment-types and tumor cell analytes for assessing treatment outcomes across multiple indications.