2. Academic Validation
  3. Discovery of a novel third-generation EGFR inhibitor and identification of a potential combination strategy to overcome resistance

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

  • Mol Cancer. 2020 May 13;19(1):90. doi: 10.1186/s12943-020-01202-9.
Tao Zhang  # 1,  Rong Qu  # 1,  Shingpan Chan  # 2,  Mengzhen Lai 1 3,  Linjiang Tong 1,  Fang Feng 1,  Hongyu Chen 4,  Tingting Song 4,  Peiran Song 1,  Gang Bai 1 5 6,  Yingqiang Liu 1 3,  Yanan Wang 1,  Yan Li 1,  Yi Su 1,  Yanyan Shen 1,  Yiming Sun 1,  Yi Chen 1,  Meiyu Geng 1,  Ke Ding 7,  Jian Ding 8,  Hua Xie 9
Affiliations

Affiliations

  • 1 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 2 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemistry Drug Development, School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510632, China.
  • 3 School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China.
  • 4 Jiangsu Aosaikang Pharmaceutical Co.Ltd (ASK pharm), 699 Kejian Road, Nanjing, 211112, China.
  • 5 University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing, 100049, China.
  • 6 School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China.
  • 7 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemistry Drug Development, School of Pharmacy, Jinan University, No. 601 Huangpu Avenue West, Guangzhou, 510632, China. dingke@jnu.edu.cn.
  • 8 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. jding@simm.ac.cn.
  • 9 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. hxie@simm.ac.cn.
  • # Contributed equally.
PMID: 32404161 DOI: 10.1186/s12943-020-01202-9
Abstract

Background: Non-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 EGFR T790M mutation. The discovery of third-generation EGFR inhibitors overcoming EGFR T790M and their new resistance mechanisms have attracted much attention.

Methods: We 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.

Results: We identified compound ASK120067 as a novel inhibitor of EGFR T790M, with selectivity over EGFR WT. ASK120067 exhibited potent anti-proliferation activity in tumor cells harboring EGFR T790M (NCI-H1975) and sensitizing mutations (PC-9 and HCC827) while showed moderate or weak inhibition in cells expressing EGFR WT. Oral administration of ASK120067 induced tumor regression in NSCLC xenograft models and in a PDX model harboring EGFR T790M. 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.

Conclusions: Our 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.

Keywords

Ack1; Drug resistance; EGFR T790M; Non-small cell lung cancer (NSCLC); Small-molecule inhibitor.

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