Abstract 1600: Tracking adaptation and response to targeted therapies in EGFR-mutant non-small cell lung cancer

Abstract Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer cases, with EGFR-mutant NSCLC among never smokers being particularly prevalent in Asian populations. A major clinical challenge in treating advanced NSCLC is the development of resistance to targeted tyrosine kinase inhibitors (TKIs), highlighting the need to comprehensively profile the cellular mechanisms underlying drug resistance. We propose to tackle this by investigating the adaptive features of residual cancer cells and the role of the tumour microenvironment in sustaining tumour growth, resistance, and disease progression. In this study, we utilise single nucleus and spatial transcriptome profiling to decipher the response of EGFR-mutant tumours in more than 30 NSCLC patients before and during on-TKI treatment, including those that have developed resistance. We present an analytical framework that maps individual residual cancer cell populations that persist after treatment. We then examine the functional phenotypes of neighbouring immune cells including T lymphocytes and mononuclear phagocytes on these populations, and then comparing the immune dynamics to tumours that have fully acquired resistance. Our study reveals a potential mechanism by which metabolic plasticity and paracrine signaling from myeloid cells in the lung tumour microenvironment contribute to the maintenance of cancer stem cell properties, likely driving disease recurrence. We propose to incorporate a wider range of ongoing clinical trial and preclinical data to support our current findings, and with the aim of defining novel therapeutic strategy that can selectively eliminate drug tolerant persister population in EGFR-mutant NSCLC. Citation Format: Regina Hoo, Aaron Tan, Dawn Lau, Komal Gupta, Kenneth Chow, Jia Chi Yeo, Lan Ying Wang, Poh Sheng Joe Yeong, Anders J. Skanderup, Daniel S. Tan. Tracking adaptation and response to targeted therapies in EGFR-mutant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1600.