Abstract A099: NXP900, a novel YES1/SRC kinase inhibitor currently in clinical development, potently inhibits tumor growth in <i>FAT1</i> mutated xenograft models

Abstract Background: NXP900 (eCF506) is a highly-potent SRC family kinase (SFK) inhibitor (IC50 of 0.47 nM against YES1) which has previously demonstrated high SFK selectivity and the capability to lock the native “closed” conformation (type 1.5 inhibitor), resulting in inhibition of both enzymatic and scaffolding activities1. Conversely, multi-kinase inhibitors dasatinib and bosutinib target the “open” conformation (type 1), thus promoting SFK association with signalling partners and as a consequence inducing a paradoxical enhancement of SFK activity as the inhibitor’s dissociates from the ATP site2. FAT atypical cadherin 1 (FAT1), a tumor suppressor gene encoding protocadherin, is among the most frequently mutated genes in human cancers. Loss of FAT1 in various tumor cells, including in lung cancer cells, results in increased protein levels of the hippo pathway transcriptional regulators YAP1 and TAZ. In turn, this increase leads to increased expression of YAP1/TAZ pro-oncogenic target genes, resulting in increased tumor cell proliferation3. Furthermore,FAT1 loss contributes to whole-genome doubling through the dysregulation of YAP14. Nuclear localization and full activation of YAP1 is also regulated by direct phosphorylation by YES15, hence we hypothesized that FAT1 mutated models would be sensitive to NXP900. Materials and methods: Cell confluence and viability were determined by automated image analysis of confluence and Presto Blue assay, respectively. FAT1 mutated cells were treated with NXP900 for 24 hours prior to fixation and subsequent immunostaining with anti-YAP, anti-YES1, phalloidin and Hoechst. Images were analysed using ImageJ software. Cell proliferation assay: for each cell line the optimal cell density was determined and used. Cells were treated with NXP900 for 120 h. Mice were treated by oral gavage with NXP900 or vehicle after reaching a 100mm3 threshold volume. Results: NXP900 showed dose-dependent decrease in YAP1 nuclear localization and prevented SRC auto-phosphorylation at low nM concentrations. In addition, NXP900 potently inhibited tumor growth of FAT1 mutated xenografts. Conclusions: NXP900 prevents YAP1 nuclear localization and inhibits SRC phosphorylation at concentrations that have been demonstrated to be clinically achievable in plasma and well tolerated in a phase 1 dose escalation study. Our data suggests that NXP900 has therapeutic potential as single agent in FAT1 mutated cancers. A Phase1b expansion study in patients with FAT1 and other genomic alterations in solid tumors is ongoing. 1)Temps et al., Cancer Res., 2021, 81, 5438-5450. 2)Higuchi et al., Cell Rep, 2021, 34, 108876. 3)Li et al., PloS One, 2025, 20, e0325535. 4)Lu et al., Nat. Cell Biol., 2025, 27, 154-168. 5)Zhao et al., Cell Chem. Biol., 2021, 28, 1235-1241. Citation Format: Boback Kaghazchi, Enrique Poradosu, Neil O. Carragher, Asier Unciti-Broceta. NXP900, a novel YES1/SRC kinase inhibitor currently in clinical development, potently inhibits tumor growth in FAT1 mutated xenograft models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A099.