Found 1 Presentation For Request "1174P"
1174P - The MET inhibitor ABN401 in combination with the third-generation EGFR-TKI is effective MET-amplified and EGFR-mutant NSCLC with acquired resistance to third-generation EGFR-TKI in preclinical models
- Mi Ra Yu (Seoul, Korea, Republic of)
Abstract
Background
ABN401 is a highly selective MET kinase inhibitor, demonstrates a safety profile in the clinical study, and remarkably inhibits tumor cell harboring MET alterations. MET gene amplification is the most frequent cause of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in non-small cell lung cancer (NSCLC) patients. Combining therapy of MET-TKI and EGFR-TKI has emerged as a promising therapeutic strategy to overcome EGFR-TKI resistance, but its mechanism and efficacy remain controversial. This study aimed to elucidate the clues of promising strategy by studying a combination of ABN401 with third-generation EGFR-TKI on MET amplified EGFR-TKI resistance model.
Methods
The signal transduction inhibition and cytotoxic response of ABN401 in combination with Lazertinib were tested in vitro against Osimertinib-resistance NSCLC cell lines (HCC827-AR) and patient-derived organoid (YUO-010), analyzed by western blot and Cell Titer-Glo assay. The in vivo efficacy study was evaluated in two patient-derived xenograft (PDX) models (YHIM-1035 and YHIM-1053). These models have been well-established and assessed gene copy number of MET by whole-exome sequencing or quantitative relative real-time polymerase chain reaction.
Results
The gene copy number of MET and EGFR mutations in HCC827-AR (MET, 22 copies; EGFR, Ex19del), YUO-010 (MET, 8 copies; EGFR, Ex19del and T790M loss), YHIM-1035 (MET, 33 copies; EGFR, Ex19del and T790M loss), and YHIM-1053 (MET, 23 copies; EGFR, Ex19del and T790M) were confirmed. ABN401 showed preclinical anti-tumor activities combined with Lazertinib (a 3rd-generation EGFR-TKI) in an EGFR mutant NSCLC model with MET gene amplification both in vitro and in vivo. Notably, in MET gene amplification (PDX model YHIM-1035, gefitinib/Osimertinib resistant), ABN401 alone showed a potent therapeutic effect.
Conclusions
Our findings suggest that the clinical application of ABN401 in combination with a third-generation EGFR-TKI to NSCLC patients with MET gene amplification can provide a promising therapeutic strategy for overcoming acquired resistance to EGFR-TKIs.
Legal entity responsible for the study
The authors.
Funding
Abion, Inc.
Disclosure
All authors have declared no conflicts of interest.