LS-106, a novel EGFR inhibitor targeting C797S, exhibits antitumor activities both in vitro and in vivo

  • Cancer Sci. 2022 Feb;113(2):709-720. doi: 10.1111/cas.15229.
Yingqiang Liu  1  2 ,  Mengzhen Lai  1  2 ,  Shan Li  3 ,  Yanan Wang  2 ,  Fang Feng  2 ,  Tao Zhang  2 ,  Linjiang Tong  2 ,  Mengge Zhang  2  4 ,  Hao Chen  3 ,  Yi Chen  2  4 ,  Peiran Song  2  5 ,  Yan Li  2 ,  Gang Bai  2 ,  Yi Ning  2  4 ,  Haotian Tang  2  4 ,  Yan Fang  2  4 ,  Yi Chen  2  4 ,  Xiaoyun Lu  3 ,  Meiyu Geng  2  4  6 ,  Ke Ding  3 ,  Ker Yu  1 ,  Hua Xie  2  4  5  6 ,  Jian Ding  1  2  4  6
Affiliations
  • 1. Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
  • 2. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 3. International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, Guangzhou, China.
  • 4. University of Chinese Academy of Sciences, Beijing, China.
  • 5. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China.
  • 6. Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
PMID: 34855271 DOI: 10.1111/cas.15229
Abstract

With the wide clinical use of the third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib for the treatment of EGFR-mutated non-small cell lung Cancer (NSCLC), acquired resistance caused by EGFR C797S tertiary mutation has become a concern. Therefore, fourth-generation EGFR inhibitors that could overcome this mutation have gained increasing attention in recent years. Here, we identified LS-106 as a novel EGFR Inhibitor against C797S mutation and evaluated its antitumor activity both in vitro and in vivo. In cell-free assay, LS-106 potently inhibited the kinase activities of EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S with IC50 values of 2.4 nmol/L and 3.1 nmol/L, respectively, which was more potent than osimertinib. Meanwhile, LS-106 exhibited comparable kinase inhibitory effect to osimertinib on EGFRL858R/T790M and wild-type EGFR. Results from cellular experiments demonstrated that LS-106 potently blocked the phosphorylation of EGFR C797S triple mutations in the constructed BaF3 cells that highly expressed EGFR19del/T790M/C797S or EGFRL858R/T790M/C797S , and thus inhibited the proliferation of these cells. We also constructed tumor cells harboring EGFR19del/T790M/C797S (named PC-9-OR cells) using the CRISPR/Cas9 system and found that LS-106 markedly suppressed the activation of EGFR19del/T790M/C797S and the proliferation of PC-9-OR cells. Moreover, cells harboring EGFR19del/T790M/C797S underwent remarkable Apoptosis upon LS-106 treatment. In vivo experiments further demonstrated that oral administration of LS-106 caused significant tumor regression in a PC-9-OR xenograft model, with a tumor growth inhibition rate (TGI) of 83.5% and 136.6% at doses of 30 and 60 mg/kg, respectively. Taken together, we identified LS-106 as a novel fourth-generation EGFR Inhibitor against C797S mutation and confirmed its preclinical antitumor effects in C797S-triple-mutant tumor models.

Keywords
C797S; epidermal growth factor receptor; fourth-generation EGFR TKI; non-small cell lung cancer; osimertinib resistance.
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