Abstract PS4-06-07: Yes/src kinase inhibitor nxp900, currently in clinical development, combines synergistically with fulvestrant against luminal a breast cancer cell lines in vitro and in vivo

Abstract Background. Most breast cancer patients present tumors with high estrogen receptor levels (ER+), which make endocrine therapies (ET) the standard of care for this breast cancer subtype. However, resistance to treatment inevitably develops over time, which demands optimal combination strategies. The combination of CDK4/6 inhibitors with ET has emerged as the foremost therapeutic modality for hormone receptor-positive/HER2-negative advanced breast cancer. However, resistance to these therapies eventually develops with the clinical benefit of subsequent lines of therapy being limited and short lasting. Deregulation of the Hippo pathway leading to YAP1 nuclear translocation has been shown to promote resistance to CDK4/6 inhibitors. NXP900 (eCF506), is a novel, highly potent, YES/SRC kinase inhibitor with high selectivity that uniquely binds the kinase in the autoinhibited closed conformation, thereby blocking its catalytic and scaffolding properties [1]. Preclinical studies have demonstrated that NXP900 effectively inhibits YAP1 nuclear translocation and proliferation of FAT1 mutated cells [2]. In addition, NXP900 demonstrated potent inhibition of cell proliferation of induced endocrine resistance in vitro [3], thus, establishing the hypothesis that NXP900 may represent a therapeutic option for the treatment of endocrine and/or CDK4/6 resistance breast cancer. The aims of this project were to (i) investigate the sensitivity of luminal A cell lines to NXP900 as a single agent, and (ii) assessing NXP900’s efficacy in combination with endocrine therapy in vitro and in vivo in comparison to current approved combinations of endocrine therapy and CDK4/6 inhibitors. Methods. Cell proliferation and viability were determined by automated image analysis of confluence and Presto Blue assay, respectively. Dose response studies were performed for NXP900, dasatinib and fulvestrant in a library of ER+ luminal A cell lines. Western blot analysis was performed to study target inhibition. Dose-ratio combinations of; NXP900 and fulvestrant; dasatinib and fulvestrant, and CDK4/6 inhibitors and fulvestrant, were used to compare the effect of each combination. In vivo xenograft studies were performed for the combination of fulvestrant and NXP900. Results. NXP900 showed higher antiproliferative activity than dasatinib against the luminal A breast cancer cell lines tested. Notably, in these cell lines NXP900 demonstrated far superior SRC/YES inhibition than dasatinib, correlating with the cancer cell viability data. Dose ratio matrix drug combination 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 dasatinib or CDK4/6 inhibitors. Conclusions. Our results demonstrate that luminal A cancer cell lines are generally sensitive to NXP900 treatment and that in combination with endocrine therapy it is more synergistic than the standard-of-care combination of fulvestrant and CDK4/6 inhibitors. This study supports the potential translation of NXP900 into breast cancer patients alongside endocrine therapies to improve the treatment of ER+ tumors. References [1] Temps et al. A Conformation Selective Mode of Inhibiting SRC Improves Drug Efficacy and Tolerability. Cancer Res. 2021, 81 (21), 5438-5450. [2] Kaghazchi et al. NXP900, a novel YES1/SRC kinase inhibitor currently in clinical development, blocks YAP1 signaling in NSCLC cell lines. Cancer Res. 2025, 85 (8, Suppl_1), 5599. [3] Lanzagorta-Calvillo et al. Endocrine therapy-resistant luminal A breast cancer cell lines are sensitive to the novel YES1/SRC tyrosine kinase inhibitor, NXP900. Cancer Res. 2025, 85 (8, Suppl_2), LB292. Citation Format: I. Lanzagorta-Calvillo, B. Kaghazchi, E. Poradosu, N. O. Carragher, A. Unciti-Broceta. Yes/src kinase inhibitor nxp900, currently in clinical development, combines synergistically with fulvestrant against luminal a breast cancer cell lines in vitro and in vivo [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-06-07.