Back to Search Start Over

The reversible fourth-generation EGFR tyrosine kinase inhibitor OBX02-011 overcomes C797S-mediated resistance in lung cancer

Authors :
Yun Jung Choi
Da-Som Kim
Young Hoon Sung
Dong Ha Kim
Kyungtaek Im
Hyeonjeong Lee
Chae Won Lee
Jeongin Cho
Joongkee Min
Dong-Cheol Woo
Sung-Eun Kim
Sunho Lee
Yun Jeong Kong
Hyung Chul Ryu
Jae-Sun Kim
Rajesh Rengasamy
Wonjun Ji
Chang-Min Choi
Jae Cheol Lee
Jin Kyung Rho
Source :
Cancer research.
Publication Year :
2022

Abstract

Osimertinib is an irreversible third-generation EGFR tyrosine kinase inhibitor (TKI) that was initially developed to overcome the EGFR T790M mutation and is used as a standard therapy in patients with advanced non–small cell lung cancer (NSCLC) with EGFR-activating mutations. Despite the remarkable initial efficacy, osimertinib, like other EGFR-TKIs, is limited by the emergence of acquired resistance. As the EGFR mutation C797S has been identified as a key driver of acquired resistance to osimertinib, development of a drug that targets this clinically relevant mutation could help improve patient outcomes. Here, we report the discovery and preclinical efficacy of OBX02–011, a reversible fourth-generation EGFR-TKI that overcomes the EGFR C797S mutation. Compared with approved EGFR-TKIs, OBX02–011 showed potent anticancer effects and inhibited EGFR-related signaling in various models, including those harboring the EGFR C797S mutation. In addition, in transgenic mouse models (EGFRL858R/T790M/C797S), OBX02–011 treatment effectively inhibited tumor growth and EGFR activity, leading to enhanced survival. Collectively, these results suggest that OBX02–011 may be a promising new EGFR-TKI to overcome C797S-mediated resistance in NSCLC. Significance: OBX02–011 is designed to target EGFR C797S and can overcome EGFR double and triple mutations to effectively treat lung cancer.

Subjects

Subjects :
Cancer Research
Oncology

Details

ISSN :
15387445
Database :
OpenAIRE
Journal :
Cancer research
Accession number :
edsair.doi.dedup.....44440363dc0ade7782882c600e9f4653