2. Academic Validation
  3. Targeted KRASG12V Degradation in vivo Elicits Lung Adenocarcinoma Regression with Subsequent Relapse from Dysregulated Proteolysis

Targeted KRASG12V Degradation in vivo Elicits Lung Adenocarcinoma Regression with Subsequent Relapse from Dysregulated Proteolysis

  • Cancer Res. 2026 May 27:10.1158/0008-5472.CAN-25-5172. doi: 10.1158/0008-5472.CAN-25-5172.
Alberto Martín 1,  Inés M García-Pérez 2,  Sonia San José 3,  Pep Rojo 2,  Carlos Riego-Mejías 2,  Cristina Teodosio 1,  Bárbara Mg Barbosa 2,  Carolina Sánchez-Zarzalejo 2,  Ignasi Folch-I-Casanovas 2,  Antonia Odena-Caballol 2,  Sònia Jarió 2,  Sara Hijazo-Pechero 2,  Silvia M Rodríguez-López 4,  Rodrigo Entrialgo-Cadierno 5,  Marie-Julie Nokin 6,  José M Muñoz-Félix 1,  Diana Loa 1,  Elizabeth Guruceaga 7,  Camille Stephan-Otto Attolini 8,  Chiara Ambrogio 9,  Alberto Villanueva 10,  Silvestre Vicent 5,  Antoni Riera 2,  David Santamaría 11,  Cristina Mayor-Ruiz 2
Affiliations

Affiliations

  • 1 University of Salamanca Salamanca Spain.
  • 2 Institute for Research in Biomedicine Barcelona Spain.
  • 3 University of Salamanca Spain.
  • 4 Centro de Investigación del Cáncer Salamanca Spain.
  • 5 Center for Applied Medical Research (CIMA), University of Navarra Pamplona, Navarra Spain.
  • 6 University of Liège Liège Belgium.
  • 7 Center for Applied Medical Research (CIMA), University of Navarra Pamplona Spain.
  • 8 Institute for Research in Biomedicine Barcelona, Barcelona Spain.
  • 9 University of Turin Turin, TO Italy.
  • 10 Catalan Institute of Oncology Spain.
  • 11 Consejo Superior de Investigaciones Científicas (CSIC) Salamanca Spain.
PMID: 42200804 DOI: 10.1158/0008-5472.CAN-25-5172
Abstract

Recent drug discovery breakthroughs led to the approval of KRASG12C inhibitors in lung adenocarcinoma (LUAD). Unfortunately, clinical responses are often hampered by the rapid resistance onset. Proteolysis-targeting chimeras (PROTACs) have emerged as promising alternatives to traditional inhibition. However, there is limited mechanistic understanding of KRAS degradation in vivo. Here, we developed a preclinical LUAD mouse model and demonstrated that targeted oncogenic KRAS degradation induces rapid tumor regression primarily due to Cancer cell-autonomous mechanisms. Yet, transcriptional, histological, and immunophenotypic analyses revealed a substantial remodeling of the tumor microenvironment. Notably, disease relapse observed during prolonged PROTAC treatment stemmed mostly from proteolysis machinery dysregulation, indicating resistance mechanisms distinct from those reported upon KRAS inhibition. Collectively, these findings highlight the therapeutic potential of KRAS degradation in LUAD, providing insights into both cell-intrinsic and -extrinsic mechanisms that accompany antitumor responses and support the ongoing clinical exploration of this approach.

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