A Preclinical Study Of Osimertinib(AZD9291) Combined With Radiation For EGFR T790M Mutant Nonsmall Cell Lung Cancer

Osimertinib(AZD9291)is a third generation of epidermal growth factor receptor(EGFR)tyrosine kinase inhibitor and has demonstrated significant clinical benefit for patients with EGFR-sensitizing mutations or the T790 M mutation.However,the potential therapeutic effect of osimertinib combined with ionizing irradiation(IR)is not well understood.In the present study,we investigated osimertinib combined with IR in EGFR T790 M non-small cell lung cancer(NCI-H1975)in vitro and in vivo.It was found that osimertinib inhibited proliferation and clonogenic survival after irradiation,decreased G2/M phase arrest in irradiated cells,and delayed DNA damage repair in a concentration-and time-dependent manner.Furthermore,osimertinib alone or combined with IR blocked phosphorylation of EGFR(Tyr1068/Tyr1173),AKT and ERK.Osimertinib also enhanced the anti-tumor activity of IR in tumor-bearing nude mice.The present study suggests that osimertinib has potential for therapeutic impact as a radiation-sensitizer in lung cancer cells harboring the EGFR T790 M mutation,providing a rationale for clinically combining osimertinib with irradiation in EGFR T790 M non-small cell lung cancer.