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

Abstract

Osimertinib is an irreversible third-generation epidermal growth factor receptor (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 to approved EGFR TKIs, OBX02-011 showed potent anticancer effects and inhibited EGFR-related signaling in various models, including those harboring the EGFR C797S mutation. Additionally, 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.

• 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
• Journal: Cancer research (Cancer Res) (Jun 14 2022) ISSN: 1538-7445 [Electronic] United States
• PMID: 35700239 (Publication Type: Journal Article, Retracted Publication)