Influence of alectinib and crizotinib on ionizing radiation - in vitro analysis of ALK/ROS1-wildtype lung tissue cells

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2022-05, Vol.27, p.100780-100780, Article 100780
• Main Authors: Jost, Tina, Schultz, Ann-Kristin, Frey, Benjamin, Vu, Jennifer, Fietkau, Rainer, Distel, Luitpold V., Hecht, Markus
• Format: Article
• Language: English
• Subjects: Alectinib; Anaplastic Lymphoma Kinase - genetics; Anaplastic Lymphoma Kinase - metabolism; Carbazoles - pharmacology; Carbazoles - therapeutic use; Carcinoma, Non-Small-Cell Lung - pathology; Crizotinib; Crizotinib - pharmacology; Humans; Lung - metabolism; Lung cells; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - radiotherapy; Normal tissue; Piperidines; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Radiation, Ionizing; Radiotherapy; Side effects
• ISSN: 1476-5586; 1522-8002; 1476-5586
• DOI: 10.1016/j.neo.2022.100780

(1) Background: Just little is known about the interaction of ALK/ROS1-targeting kinase inhibitors with ionizing radiation (IR), particularly regarding side effects. We investigated the toxicity in two different lung cell lines both ALK/ROS1 wildtype (healthy and tumor origin) as representatives for normal lung tissue; (2) Methods: Human lung cell line BEAS-2B and malignant A549 lung cancer cells (ALK/ROS1 wt) were treated with alectinib or crizotinib, 2 Gy irradiation or a combination of KI and IR. Cell toxicity was analyzed by cell death (Annexin, 7AAD), colony forming, migration assay and live-cell imaging (TMRM, DRAQ7, Caspase3/7). Cell cycle (Hoechst) were analyzed by flow cytometry; (3) Results: Crizotinib led to higher cell death rates than alectinib, when cells were treated with 10 µM KI. Alectinib induced a more intense growth inhibition of colonies. Both inhibitors showed additive effects in combination with irradiation. Combination treatment (IR + KI) does not lead to synergistic effect on neither cell death nor colony forming; (4) Conclusions: The influence of simultaneous KI and IR was studied in non-mutated ALK/ROS1 cell lines. Both KIs seems to be well tolerated in combination with thoracic radiotherapy and lacked synergistic reinforcement in cellular toxicity. This supports the feasibility of ALK/ROS1 inhibition in combination with thoracic irradiation in future clinical trials.