Abstract 4029: JIN-A04, highly effective tyrosine kinase inhibitor targeting HER2 exon 20 insertion mutations in NSCLC
Authors: Yu Mi Ra , Yun Mi Ran , Lee Jii Bum , Lee Ji Yun , Aum So Won , Choi Su Jin , Park Ju Yeon , Oh Seung Yeon , Lee Eun Ji , Duggirala Krishna Babu , Lee Kwangho , Hong Min Hee , Lim Sun Min , Jo Anna , Seah Ethan , Kim Choonok , Cho Byoung Chul 
Published: April 2023

Abstract
Introduction: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 85% of lung cancer patients. 2% - 4% of patients with NSCLC harbor human epidermal growth factor receptor 2 gene (HER2) mutations, being the 90 % of them exon 20 insertions. The most common HER2 mutations in NSCLC are exon 20 mutation A775_G776insYVMA (YVMA) mutation in the kinase domain. Currently, treatment options for this subset of patients are limited. JIN-A04 is an orally available tyrosine kinase inhibitor (TKI) targeting HER2 exon20 insertion mutations and has the potential to be a best-in-class drug candidate to address this unmet clinical need.
Method: The inhibitory activity of JIN-A04 was evaluated by cell viability assay in both Ba/F3 cell lines expressed HER2 YVMA and HER2 P780_Y781insGSP (GSP) mutations. Also, Ba/F3 HER2 wild-type (WT) and normal cell lines for HUVEC (endothelial cells) and BEAS-2B (human bronchial epithelial cells) were used to assess cellular activity. In addition, to confirm mechanism action, western blotting analysis was performed on Ba/F3 YVMA and Ba/F3 GSP cell lines.
Results: In cell viability assay, JIN-A04 strongly inhibited cellular activity against Ba/F3 cell lines engineering to express the mutants HER2 YVMA (IC50 = 11.1 nM) and GSP (IC50 = 1.4 nM). It was superior to Mobocertinib (IC50 = 27.1 nM for YVMA and IC50 = 3.3 nM for GSP) and comparable with Poziotinib (IC50 = 3.4 nM for YVMA and IC50 = 0.4 nM for GSP). In normal cell lines, JIN-A04 did not inhibit the activity of HUVEC (IC50 = &gt 1000 nM) and BEAS-2B (IC50 = &gt 1000 nM) cell lines, largely sparing HER2 WT activity (IC50 = &gt 1000 nM). In protein expression analysis, JIN-A04 was effectively inhibited in all signaling pathway of p-EGFR, p-AKT, p-ERK1/2, and p-S6 on Ba/F3 YVMA and Ba/F3 GSP cell lines at a low dose level.
Conclusion: JIN-A04 is highly potent against HER2 exon 20 insertion mutations including YVMA and GSP, while largely sparing HER2 WT activity. Also, JIN-A04 demonstrated effective HER2 pathway inhibition. Based on these robust activities for HER2 exon 20 insertion, JIN-A04 is expected to provide a potent therapeutic opportunity for NSCLC patients with HER2 exon20 insertion mutations.
Citation Format: Mi Ra Yu, Mi Ran Yun, Jii Bum Lee, Ji Yun Lee, So Won Aum, Su Jin Choi, Ju Yeon Park, Seung Yeon Oh, Eun Ji Lee, Krishna Babu Duggirala, Kwangho Lee, Min Hee Hong, Sun Min Lim, Anna Jo, Ethan Seah, Choonok Kim, Byoung Chul Cho. JIN-A04, highly effective tyrosine kinase inhibitor targeting HER2 exon 20 insertion mutations in NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4029.