Abstract 7203: Anti-HDGF antibody attenuates the rise of resistance to EGFR tyrosine kinase inhibitor in NSCLC patient-derived xenograft tumors

Abstract Mutant epidermal growth factor receptor (EGFR), a major oncogenic driver in non-small cell lung cancer (NSCLC), is found in the tumors of 15% (western countries) to 50% (Asian countries) of patients. EGFR-targeted therapy using tyrosine kinase inhibitors (TKIs) is a standard of care for those patients who developed metastatic or recurrent diseases. However, despite having an 80% initial response rate, most patients had partial tumor regression and their disease would progress when acquired resistance emerges. Thus, developing more effective treatment is an unmet need. The clinical response of these patients can be recapitulated in mouse models of patient-derived xenograft (PDX) tumor bearing sensitizing EGFR mutations. In this study, treating established PDX tumors with osimertinib, a third generation EGFR TKI, induced partial tumor regression (50% to 70% size reduction from baseline) followed by progression with a median progression-free survival (PFS) of 26 to 28 days. Interestingly, co-administering an antibody against hepatoma-derived growth factor (HDGF) with osimertinib resulted in enhanced tumor regression (98% to 100% size reduction from baseline) which translated into significantly extended animal survival with a median PFS of 103 or 135 days. Immunohistochemical and western blot examination of tumors collected at different treatment timepoints indicated that AKT/mTOR and MAPK pathways were reactivated after initial suppression in TKI monotherapy arm despite persistent EGFR inhibition. Since AKT/mTOR and MAPK pathways are key survival and proliferative signaling pathways, their reactivation can promote TKI tolerance of tumor cells and the emergence of TKI resistance. However, blocking HDGF attenuated the reactivation of these pathways which could partially explain the enhanced efficacy of osimertinib plus anti-HDGF antibody combination treatment seen in this study. Our results suggest tumor-derived HDGF could play a crucial role in the rise of acquired resistance to osimertinib. Identifying the exact cells and molecular pathways utilized by HDGF to promote tumor cell tolerance to TKI will help us understand how TKI sensitive tumor cells survive EGFR blockade and emerge as resistant cells. Citation Format: Cindy Q. Zhou, Ariel Li, Kaoru Ri, Ahmed Sultan, Hening Ren. Anti-HDGF antibody attenuates the rise of resistance to EGFR tyrosine kinase inhibitor in NSCLC patient-derived xenograft tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7203.