P65-047, a novel TEAD degrader, overcomes KRAS inhibitor resistance through Hippo pathway disruption in NSCLC

Abstract

Background: Allele-specific KRAS inhibitors (e.g. MRTX849, MRTX1133) show clinical benefit in KRAS-mutant NSCLC but face rapid development of resistance mediated by adaptive YAP/TEAD axis activation. TEAD degraders represent a rational mechanistic partner to intercept this bypass pathway and restore KRAS inhibitor sensitivity.
Methods: P65-047, a cereblon-recruiting TEAD degrader, was evaluated in: (1) in vivo subcutaneous CDX models using NCI-H226 (NF2-/- mesothelioma, Hippo-dysregulated) and CALU-1 (KRASG12C/TP53-/- NSCLC); and (2) in vitro KRASG12D(LA1)/p53R172HΔG/+ (KP) syngeneic NSCLC mouse models including 344SQ-G12D and 344SQ-G12C (CRISPR/Cas9 modified to KRASG12C). Parental and MRTX1133/MRTX849-resistant derivatives were utilized. TEAD protein degradation and target gene suppression were assessed by Western blot and qPCR.
Results: P65-047 monotherapy induced dose-dependent tumour regression in both xenograft models (vehicle-treated tumours progressed). In resistant cell models, P65-047 exhibited minimal single-agent activity but produced marked restoration of KRAS inhibitor-dependent growth suppression in combination settings: P65-047 + MRTX1133 resensitized MRTX1133-resistant 344SQ-M1133R cells, and P65-047 + MRTX849 resensitized MRTX849-resistant 344SQ-M849R cells in cell viability assays. Mechanistic studies confirmed on-target TEAD degradation and suppression of TEAD-regulated transcripts in resistant cells.
Conclusions: P65-047 displays high efficacy, delivering robust in vivo tumour regression and strong resensitization in vitro, establishing TEAD degradation as a mechanistically validated strategy to overcome acquired resistance in KRAS-mutant NSCLC. These data support clinical advancement of TEAD degraders in patients with allele-specific KRAS inhibitor-refractory disease.

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