Abstract 7030: Tumor-macrophage crosstalk promotes resistance to EGFR targeted therapy in lung adenocarcinoma.

Abstract Lung cancer remains the leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) is the predominant histologic subtype, with lung adenocarcinoma the most common form of NSCLC. Approximately 15-20% of lung adenocarcinomas harbor activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). Although targeted therapies have substantially improved clinical outcomes for patients with EGFR-mutant NSCLC, most patients do not achieve complete response, underscoring the need to elucidate mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs). We hypothesize that, in addition to tumor-cell-intrinsic mechanisms, interactions between cancer cells and the tumor microenvironment could contribute to treatment resistance. Leveraging clinical sequencing data alongside cell co-culture systems, organoid models, and in vivo studies, we show that TKI-treated EGFR-mutant cells upregulate cytokines and chemokines that promote recruitment and maintenance of tumor-infiltrating macrophages, a population associated with poor clinical outcomes. Moreover, interactions between therapy-treated cancer cells and newly recruited macrophages support tumor survival by enhancing cancer cell viability and reducing phagocytic clearance. Genetic and molecular profiling further reveal that soluble pro-inflammatory mediators secreted by macrophages, including TNF-ɑ and IL-1β, engage the NF-κB signaling pathway in EGFR-mutant cells, thereby driving residual disease and resistance. Together, these findings provide a rationale for disrupting microenvironmental crosstalk between EGFR-mutant tumor cells and tumor-infiltrating macrophages as a strategy to limit residual disease. Targeting these interactions may enable a new class of microenvironment-directed therapies to overcome resistance to EGFR TKIs. Citation Format: Philippe Gui, Victor Olivas, Tiffany Li, Whitney Tamaki, Hannah Bergo, D. Lucas Kerr, Wei Wu, Collin M. Blakely, Trever G. Bivona. Tumor-macrophage crosstalk promotes resistance to EGFR targeted therapy in lung adenocarcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7030.