Targeting PDK and PARP to improve radiation response in preclinical models of non-small cell lung cancer

Abstract

Approximately 50 % of all NSCLC patients receive radiation therapy during the course of their disease, and the quest to enhance the radiation response of these patients is still ongoing. Here, we investigate the potential to increase the radiation response of NSCLC by targeting the PI3K signalling pathway with PDK1 inhibitors and/or targeting DNA repair with the PARP inhibitor olaparib. The in vitro radiosensitising effect of the PARP inhibitor olaparib and the PDK1 inhibitors BX912 and GSK2334470 was determined using clonogenic survival assays. The combination of PDK1 inhibitors with radiation did not increase the radiosensitivity of NSCLC cell lines, irrespective of the TP53 status. However, a significant radiosensitisation was observed by addition of olaparib to radiation treatment (SER50 1.6 to 2.2). Immunofluorescent quantification of γH2AX foci formation indicated that the radiosensitisation effect of olaparib could be explained by inhibition of DNA repair. Subsequently, we demonstrated that olaparib enhances the radiosensitivity of a poorly vascularised NSCLC xenograft model by decreasing DNA repair and increasing apoptosis. In contrast, a well vascularised NSCLC model was not sensitised by addition of olaparib to radiation treatment. The effect of olaparib on in vivo vascular perfusion was assessed using dynamic contrast enhanced-magnetic resonance imaging. No significant differences were observed between olaparib and vehicle treated xenografts, suggesting that the radiosensitising effect can be mainly attributed to inhibition of DNA repair. We demonstrated that olaparib is a potent radiosensitiser in a poorly vascularised lung cancer model but further in vivo experiments are warranted to identify the subset of patients that would benefit from olaparib addition to radiation therapy.This thesis is not currently available in ORA