Alberto Martín, Inés M. García-Pérez, Sonia San José, Pep Rojo, Carlos Riego‐Mejías, Cristina Teodosio, Bárbara MG. Barbosa, Carolina Sánchez, Ignasi Folch-I-Casanovas, Antonia Odena-Caballol, Sònia Jarió, Sara Hijazo‐Pechero, Silvia M. Rodríguez-López, Rodrigo Entrialgo‐Cadierno, Marie‐Julie Nokin, José M. Muñoz-Félix, Diana Loa, Elizabeth Guruceaga, Camille Stephan‐Otto Attolini, Chiara Ambrogio, Alberto Villanueva, Silvestre Vicent, Antoni Riera, David Santamarı́a, Cristina Mayor-Ruiz
Abstract Recent drug discovery breakthroughs have led to the approval of KRASG12C inhibitors in lung adenocarcinoma. Unfortunately, clinical responses are often hampered by the rapid onset of resistance. Proteolysis-targeting chimeras (PROTAC) have emerged as promising alternatives to traditional inhibition. However, there is limited mechanistic understanding of KRAS degradation in vivo. In this study, we developed a preclinical lung adenocarcinoma mouse model and demonstrated that targeted oncogenic KRAS degradation induces rapid tumor regression primarily due to cancer cell–autonomous mechanisms. However, transcriptional, histologic, 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 lung adenocarcinoma, providing insights into both cell-intrinsic and cell-extrinsic mechanisms that accompany antitumor responses and support the ongoing clinical exploration of this approach. Significance: KRAS degradation induces rapid regression of lung adenocarcinoma tumors mainly via cancer cell-intrinsic mechanisms, offering a complementary strategy to target KRAS given the short duration of clinical responses to inhibitors. See related article by YYY, p. XX .