Reference Detail

Ref Type

PMID

Authors

Xile Liu, Xiquan Zhang, Ling Yang, Xin Tian, Tiantian Dong, Charles Z Ding, Lihong Hu, Lingyu Wu, Lele Zhao, Jun Mao, Qusheng Ji, Shaoyu Yan, Zhenzhen Zhu, Yuanfeng Xia, Chichung Chan, Shuhui Chen

Title

Preclinical evaluation of TQB3804, a potent EGFR C797S inhibitor.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Proceedings of the American Association for Cancer Research

URL

https://aacrjournals.org/cancerres/article/79/13_Supplement/1320/633459/Abstract-1320-Preclinical-evaluation-of-TQB3804-a

Abstract Text

Objective: Osimertinib is the 3rd generation EGFR inhibitor, which has been approved for the treatment of NSCLC patients with EGFRT790M. More recently, a tertiary EGFRC797S mutation was reported as the dominant resistance (40~20%) mechanism to Osimertinib. The emergence of C797S mutation prevent covalent bond formation with Osimertinib, and caused the drug resistance. So, it’s an urgent demand for new EGFR inhibitors that can effectively inhibit EGFR triple mutant, d746-750/T790M/C797S & L858R/T790M/C797S. Here, we disclose our clinical candidate, TQB3804, as a novel 4th generation inhibitor that potently inhibits triple mutants. Methods: The enzyme activities of TQB3804 for EGFRd746-750/T790M/C797S, EGFRL858R/T790M/C797S, EGFRd746-750/T790M, EGFRL858R/T790M, and EGFRWT were measured with corresponding kinase assays. The anti-proliferative activity was evaluated in Ba/F3 (EGFRd746-750/T790M/C797S), NCI-H1975 (EGFRd746-750/T790M/C797S), PC9 (EGFRd746-750), and A431 (EGFRWT) cell lines, and the phosphorylation of EGFR was also evaluated in Ba/F3 (EGFRd746-750/T790M/C797S) cell line. Antitumor activity of TQB3804 was evaluated in three triple mutant cell-derived tumor xenograft (CDX) models Ba/F3 (EGFRd746-750/T790M/C797S), NCI-H1975 (EGFRd746-750/T790M/C797S), and PC9 (EGFRd746-750/T790M/C797S) and one Osimertinib resistant patient-derived xenograft (PDX) model of NSCLC (LUPF104, EGFRd746-750/T790M/C797S). Results: TQB3804 displayed potent enzymatic activities for EGFRd746-750/T790M/C797S, EGFRL858R/T790M/C797S, EGFRd746-750/T790M, and EGFRL858R/T790M with IC50 of 0.46, 0.13, 0.26, and 0.19 nM respectively, and has similar enzymatic activity for EGFRWT (IC50 = 1.07) to Osimertinib. It also showed expected anti-proliferative activity in 4 cell lines, Ba/F3 (EGFRd746-750/T790M/C797S), NCI-H1975 (EGFRd746-750/T790M/C797S), PC9 (EGFRd746-750), and A431 (EGFRWT), with IC50 of 26.8, 163, 45, and 147 nM, respectively. The phosphorylation for EGFR in Ba/F3 (EGFRd746-750/T790M/C797S) cell line was potently inhibited with IC50 =18.5 nM. TQB3804 significantly inhibited tumor growth in the triple mutant Ba/F3 (EGFRd746-750/T790M/C797S), NCI-H1975 (EGFRd746-750/T790M/C797S), and PC9 (EGFRd746-750/T790M/C797S) CDX models, as well as in the LUPF104 PDX model. Western blot analysis of the tumor samples in the Ba/F3 (EGFRd746-750/T790M/C797S) CDX model showed that TQB3804 inhibited p-EGFR, p-AKT and p-ERK indicating that the tumor growth inhibition was through inhibition of the resistant triple mutant EGFR. Conclusions: We have identified a potent orally active 4th generation EGFR inhibitor, TQB3804. It can inhibit the activity of Osimertinib resistant triple mutant EGFR, and showed strong antitumor activity in corresponding in vitro and in vivo preclinical assays. These results are considered highly promising and warrant moving the compound forward to clinical investigation.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
TQB3804	TQB3804	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
TQB3804		TQB 3804\|TQB-3804\|EGFR-IN-7	EGFR Inhibitor (Pan) 61	TQB3804 (EGFR-IN-7) is a 4th generation EGFR inhibitor that demonstrates activity against EGFR TKI resistance mutations, and may lead to anti-tumor effect (Proceedings of the American Association for Cancer Research, Vol 60, Mar 2019, Abstract #1320).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References