Abstract 6495: NXP900, a Phase 1b, first-in-class YES1/SRC inhibitor demonstrates potent synergy with KRAS inhibitors in KRASi sensitive and resistant NSCLC models

Abstract Background: NXP900 (eCF506) is a novel potent and selective SRC family kinase (SFK) inhibitor, (IC50 of 0.47 nM against YES1). NXP900 first-in-class mode-of-action locks its target into its native “closed” conformation, thereby inhibiting both kinase activity and scaffolding function with protein signaling partners (Temps et al. Cancer Res 2021). In contrast, other clinically available inhibitors, lock SRC in the active “open” conformation promoting the association of SFK and signaling partners via allosteric facilitation (Higuchi et al. Cell Rep 2021). G12C mutant-selective KRAS inhibitors (KRASi) have been FDA-approved and several mutant-selective, pan-mutant-KRAS, and pan-RAS inhibitors are in development. However, KRASi monotherapy results in limited clinical benefit and face the rapid development of acquired resistance. YAP1 activation is associated with drug resistance to KRASi and promotes the survival of drug-tolerant persister cells after therapy. Induction of YAP1 nuclear localization by SRC/YES1 mediated tyrosine phosphorylation of YAP1 and LATS1 is inhibited by NXP900 in NSCLC cell lines at a low nM concentration. A FIH, dose escalation study, demonstrated that NXP900 potently inhibits the activity of SRC kinase at well tolerated doses (Falchook et al. Cancer Res 2025). Moreover, no CYP3A induction was observed in a drug-drug interaction study in humans indicating the potential of NXP900 to be combined with KRASi to overcome primary and acquired resistance and improve clinical benefit to patients with KRAS mutated cancers. Materials and methods: Resistant cell lines to the KRASi sotorasib were generated from NCI-H23 cells. 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. Cells were treated with KRASi and or NXP900 for 120 h and underwent ATPlite viability assay. Drug combination effects were studied using the Bliss independence principle. Results: NXP900 potently inhibited the activating SRC autophosphorylation, YAP1 nuclear localization and demonstrated synergy in combination with sotorasib in sotorasib-sensitive and resistant cell lines. Conclusions: Development of effective and tolerable combination therapies are needed to overcome resistance and maximize the clinical impact of RAS-targeted therapy. NXP900 can potently inhibit cell proliferation of KRAS mutated cell lines in combination with a KRASi in NSCLC models. The combination was synergistic both in KRAS sensitive and resistant models. The data suggests that NXP900, currently in a Phase1b expansion in patients with FAT1, YES1 and other genomic alterations in solid tumors (NCT05873686), is an attractive and translatable combination partner that could synergize with KRASi. Citation Format: Boback Kaghazchi, Enrique Podarosu, Asier Unciti-Broceta, Neil O. Carragher. NXP900, a Phase 1b, first-in-class YES1/SRC inhibitor demonstrates potent synergy with KRAS inhibitors in KRASi sensitive and resistant NSCLC models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6495.