P65-047, a novel TEAD degrader, overcomes KRAS inhibitor resistance through Hippo pathway disruption in NSCLC
Presenter: Peter Brandt Session: Late-Breaking Research: Experimental and Molecular Therapeutics 3 Time: 4/21/2026 2:00:00 PM → 4/21/2026 5:00:00 PM
Authors
Rajiv Sawant 1 , Matthis Geitmann 1 , Per Källblad 1 , Samrat T. Kundu 2 , Sofia Garza 2 , Don L. Gibbons 2 , Konrad Koehler 1 , Peter Brandt 1 1 Beactica Therapeutics, Uppsala, Sweden, 2 UT MD Anderson Cancer Center, Houston, TX
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 (KRAS G12C /TP53 -/- NSCLC); and (2) in vitro KRAS G12D(LA1) /p53 R172HΔG/+ (KP) syngeneic NSCLC mouse models including 344SQ-G12D and 344SQ-G12C (CRISPR/Cas9 modified to KRAS G12C ). 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.
Disclosure
R. Sawant, Beactica Therapeutics Employment, Stock Option, Patent. M. Geitmann, Beactica Therapeutics Employment, Stock, Stock Option. P. Källblad, Beactica Therapeutics Employment, Stock. S. T. Kundu, UT MD Anderson Cancer Center Employment. S. Garza, UT MD Anderson Cancer Center Employment. D. L. Gibbons, UT MD Anderson Cancer Center Employment. K. Koehler, Beactica Therapeutics Employment, Stock Option. P. Brandt, Beactica Therapeutics Employment, Stock Option, Patent.
Cited in
Control: 10651 · Presentation Id: 11469 · Meeting 21436