Abstract LB292: Endocrine therapy-resistant luminal A breast cancer cell lines are sensitive to the novel YES1/SRC tyrosine kinase inhibitor, NXP900

Background: The majority of patients with breast cancer present with tumors that are estrogen receptor positive (ER+), thus endocrine therapies have become the main treatment option for this type of cancer. However, endocrine resistance inevitably develops over time, resulting in an unmet clinical challenge to treat this breast cancer subtype. The novel YES1/SRC tyrosine kinase inhibitor NXP900, currently in phase 1 clinical trials, binds SRC in its ‘autoinhibited’ inactive conformation, thereby inhibiting the phosphorylation and the scaffolding properties of the kinase1. Recent findings using ER+ cell lines show increased sensitivity with NXP900 as opposed to other kinase inhibitors, such as dasatinib or bosutinib. The aim of the study was to investigate the therapeutic potential of NXP900 in combination with endocrine therapies, as well as the potential to treat ER+ cell lines with acquired endocrine resistance. Methods: ER+ cell lines were simultaneously treated with combinational dose-ratios of NXP900 and endocrine therapy, and viability determined using PrestoBlue assays. ER+ cell lines were cultured with endocrine therapy until resistance was acquired, approximately 1 year; periodical assays were undertaken during the course of the experiment to investigate mRNA abundance (RT-qPCR), drug sensitivity (cell viability), and growth (clonogenic assays) over time. Results: Statistical analysis using SynergyFinder+ demonstrated significantly stronger synergistic interactions in ER+ cell lines treated with endocrine therapy in combination with NXP900, rather than in combination with other kinase inhibitors. The longitudinal study of ER+ cell lines cultured with endocrine therapy showed continuous sensitivity to NXP900 treatment as endocrine resistance developed. Conclusions: Our results suggest that ER+ cell lines are more sensitive to endocrine therapy in combination with NXP900 rather than in combination with other kinase inhibitors. Additionally, our longitudinal data suggests that NXP900 is a strong therapeutic candidate to treat ER+ cell lines with acquired endocrine resistance. This study supports the potential translation of NXP900 into an adjuvant clinical setting, alongside endocrine therapies, to improve breast cancer treatment in patients with ER+ tumors. References 1. Temps C, Lietha D, Webb ER, et al. A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability. Cancer Res. 2021;81(21):5438-5450. doi:10.1158/0008-5472.CAN-21-0613 Citation Format: Iñigo Lanzagorta Calvillo, Enrique Poradosu, Neil Carragher, Asier Unciti-Broceta. Endocrine therapy-resistant luminal A breast cancer cell lines are sensitive to the novel YES1/SRC tyrosine kinase inhibitor, NXP900 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr LB292.