ABT-737, a BH3 Mimetic, Enhances the TherapeuEffects of Ionizing Radiation in K-ras Mutant Non-Small Cell Lung Cancer Preclinical Model

Purpose: Tumor radioresistance and dose-limiting toxicity restrict the curative potential of radiotherapy, requiring novel ap-proaches to overcome the limitations and augment the efficacy. Here, we investigated the effects of signal transducer and activator of transcription 3 (STAT3) activation and autophagy induction by irradiation on antiapoptotic proteins and the effectiveness of the BH3 mimetic ABT-737 as a radiosensitizer using K-ras mutant non-small cell lung cancer (NSCLC) cells and a Kras^G12D:p53^fl/fl mouse (KP mouse) model. Materials and Methods: A549 and H460 cells were irradiated, and the expression of Bcl-2 family proteins, JAK/STAT transcriptional pathway, and autophagic pathway were evaluated by immunoblotting. The radiosensitizing effects of ABT-737 were evaluated using A549 and H460 cell lines with clonogenic assays and also by a KP mouse model with microcomputed tomography and immunohistochemistry. Results: In A549 and H460 cells and mouse lung tissue, irradiation-induced overexpression of the antiapoptotic molecules Bcl-xL, Bcl-2, Bcl-w, and Mcl-1 through JAK/STAT transcriptional signaling induced dysfunction of the autophagic pathway. After treatment with ABT-737 and exposure to irradiation, the number of surviving clones in the cotreatment group was significantly lower than that in the group treated with radiation or ABT-737 alone. In the KP mouse lung cancer model, cotreatment with ABT-737 and radiation-induced significant tumor regression; however, body weight changes in the combination group were not significantly different, suggesting that combination treatment did not cause systemic toxicity. Conclusion: These findings supported the radiosensitizing activity of ABT-737 in preclinical models, and suggested that clinical trials using this strategy may be beneficial in K-ras mutant NSCLC.