Abstract 5984: Overcoming osimertinib resistance in NSCLC with NXP900, a phase 1, highly selective and potent first-in-class total YES1/SRC inhibitor

Background: Mutant-selective epidermal growth factor receptor (EGFR) inhibitors such as osimertinib, demonstrate potent activity in the treatment of EGFR-mutant lung cancer, unfortunately, the development of resistance to such EGFR inhibitors is nearly universal. Recent phosphoproteomic analysis has identified Src family kinase (SFK) activity as an important mechanism of osimertinib resistance (Tozuka et al. JTO Clin Res Rep. 2024, 5(4):100668). NXP900 (eCF506) is a novel potent and highly selective SRC family kinase (SFK) inhibitor, (IC50 of 0.47 nM against YES1) which possesses a unique/first-in-class binding mode-of-action. NXP900 locks its target into its native “closed” conformation (type 1.5 inhibitor), thereby inhibiting both kinase activity and complex formation with protein partners (Temps et al. Cancer Res. 2021, 81, 5438-5450). In contrast, multi-kinase inhibitors, including dasatinib and bosutinib, block SRC in the active “open” conformation (type 1 inhibitors) promoting the association of SFK and signaling partners via allosteric facilitation (Higuchi et al. Cell Rep 2021, 34, 108876). NXP900 may therefore represent an optimal drug combination partner with osimertinib to overcome acquired resistance in EGFR mutant lung cancer. Materials and Methods: Cell proliferation assay - Cells were diluted in the corresponding ATCC recommended medium and dispensed in a 384-well plate, depending on the cell line used, at a density of 100 - 6400 cells per well. To study drug combination effects, mixtures of osimertinib and NXP900 are used across three different fixed concentration ratios to calculate a combination index (CI) value to determine synergistic activity using the Oncolines SynergyFinderTM platform. In vivo studies: Mice transplanted with osimertinib resistant cell lines were treated by oral gavage with single agents or combination after reaching a 100mm3 threshold volume. Results: NXP900 and osimertinib combination treatment demonstrates statistically significant and potent synergy in osimertinib resistant NSCLC cell lines in vitro. In vivo studies demonstrate significantly increased duration of anti-cancer response to the NXP900 and osimertinib combination treatment arm relative to corresponding monotherapy arms in an EGFR mutant lung cancer model. Conclusions: Despite high response rates to osimertinib in EGFR mutant lung cancer patients acquired resistance almost universally arises. Here we demonstrate that NXP900 in combination with osimertinib demonstrates potent synergy and prolonged inhibition of tumor growth in in vitro and in vivo NSCLC models of acquired osimertinib resistance. Altogether, these data suggest that NXP900 may have therapeutic potential in EGFR mutant cancers with acquired resistance to osimertinib. A FIH, Phase1 dose escalation study for NXP900 is ongoing. Citation Format: Neil O. Carragher, Enrique Poradosu, Asier Unciti-Broceta. Overcoming osimertinib resistance in NSCLC with NXP900, a phase 1, highly selective and potent first-in-class total YES1/SRC inhibitor [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 5984.