Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance

• DOI: 10.1186/s12943-020-01202-9
• Publication Date: 2020-05-13T06:02:57Z
• Authors: Tao Zhang; Rong Qu; Shingpan Chan; Mengzhen Lai; Linjiang Tong; Fang Feng; Hongyu Chen; Tingting Song; Peiran Song; Gang Bai; Yingqiang Liu; Yanan Wang; Yan Li; Yi Su; Yanyan Shen; Yiming Sun; Yi Chen; Meiyu Geng; Ke Ding; Jian Ding; Hua Xie
• Keywords: Ack1; Lung Neoplasms; Mice, Nude; Non-small cell lung cancer (NSCLC); Apoptosis; EGFR T790M; Small-molecule inhibitor; Mice; 03 medical and health sciences; Carcinoma, Non-Small-Cell Lung; Antineoplastic Combined Chemotherapy Protocols; Drug Discovery; Tumor Cells, Cultured; Animals; Humans; Protein Kinase Inhibitors; RC254-282; Cell Proliferation; Mice, Inbred BALB C; 0303 health sciences; Research; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Xenograft Model Antitumor Assays; 3. Good health; ErbB Receptors; Drug Resistance, Neoplasm; Drug resistance; Mutation; Female

AbstractBackgroundNon-small cell lung cancer (NSCLC) patients with activating EGFR mutations initially respond to first-generation EGFR inhibitors; however, the efficacy of these drugs is limited by acquired resistance driven by the EGFRT790Mmutation. The discovery of third-generation EGFR inhibitors overcoming EGFRT790Mand their new resistance mechanisms have attracted much attention.MethodsWe examined the antitumor activities and potential resistance mechanism of a novel EGFR third-generation inhibitor in vitro and in vivo using ELISA, SRB assay, immunoblotting, flow cytometric analysis, kinase array, qRT-PCR and tumor xenograft models. The clinical effect on a patient was evaluated by computed tomography scan.ResultsWe identified compound ASK120067 as a novel inhibitor of EGFRT790M, with selectivity over EGFRWT. ASK120067 exhibited potent anti-proliferation activity in tumor cells harboring EGFRT790M(NCI-H1975) and sensitizing mutations (PC-9 and HCC827) while showed moderate or weak inhibition in cells expressing EGFRWT. Oral administration of ASK120067 induced tumor regression in NSCLC xenograft models and in a PDX model harboring EGFRT790M. The treatment of one patient with advanced EGFR T790M-positive NSCLC was described as proof of principle. Moreover, we found that hyperphosphorylation of Ack1 and the subsequent activation of antiapoptotic signaling via the AKT pathway contributed to ASK120067 resistance. Concomitant targeting of EGFR and Ack1 effectively overrode the acquired resistance of ASK120067 both in vitro and in vivo.ConclusionsOur results idenfity ASK120067 as a promising third-generation EGFR inhibitor and reveal for the first time that Ack1 activation as a novel resistance mechanism to EGFR inhibitors that guide to potential combination strategy.