Abstract 1920: PC9 AZD9291-resistant (PC9-OSIR) cell line, a useful cell model for novel drug discovery

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the leading cause of lung cancer-related mortality. Identification of EGFR as a driver gene of NSCLC has led to the development of EGFR inhibitors, such as Gefitinib, Erlotinib, Afatinib and Osimertinib (AZD9291). AZD9291, a third-generation EGFR inhibitor, has been approved as the first-line treatment for patients with EGFR T790M mutation-positive NSCLC. Resistance to AZD9291 was observed clinically and C797S mutation was reported to be a major mechanism for resistance to AZD9291.Our group has generated PC9 AZD9291-resistant (PC9-OSIR) cell line using a dose-escalation method after treatment of the cells with mutagenic agent. Specifically, PC9 cells was treated by AZD99291 with increasing dose for 2 weeks, and remaining live cells was retrieved and designated as PC9-OSIR. Cell survival assay showed that IC50 of PC9-OSIR was over 2μM, 100-fold more resistant than the parental PC9 cells. We explored the resistance mechanisms using whole exome sequencing (WES) and RNA-Seq, but did not find EGFR C797S mutation—the most common resistance mechanism to AZD9291—in PC9-OSIR, suggesting a likely novel resistance mechanism, possibly the activation of a bypass signaling pathway, which will be elucidated by further studies.The PC9-OSIR cell line can be a useful cell line model, in addition to cell lines with C797S mutation, in the development of future EGFR inhibitors. It can also be used to explore new mechanisms of resistance to AZD9291 resistance. Note: This abstract was not presented at the meeting. Citation Format: Zhaoshuai Bai, Guoqian Wang, Xiaolin Zhou, Zhongquan Mu, Feng Hao, Jinying Ning. PC9 AZD9291-resistant (PC9-OSIR) cell line, a useful cell model for novel drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1920.