Abstract 5509: Mechanisms regulating resistance to KRAS inhibitor driven by DNp63/YAP regulation of tissue stiffness and metabolic alterations in lung adenocarcinoma

Targeted therapies to the KRAS oncogene have shown significant success in treatment of lung adenocarcinoma (LuAD). Challenges emerge when tumors acquire resistance to these targeted KRAS inhibitors (KRASi). Recent studies have reported several mechanistic pathways associated with the development of resistance which includes nuclear localization of YAP. TP53 mutations are the predominant genetic changes responsible for inducing resistance to targeted therapies and chemotherapy drugs. Mutations in TP53 lead to the inhibition of the tumor and metastasis suppressor TAp63 and the activation of the oncogenic isoform ΔNp63. We have previously shown that loss of ΔNp63 in KRAS driven LuAD results in fewer tumors indicating an oncogenic role for ∆Np63 in LuAD. Here, we demonstrate that cells and tumors resistant to KRAS G12C inhibitors (KRASiR) exhibit increased expression of ∆Np63 while the sensitive cells express lower levels of ∆Np63. The KRASiR cells showed increased total and nuclear localization of YAP/TAZ along with increased expression of ∆Np63 in the nucleus. KRASiR resistant cells also had increased proliferation, mitochondrial membrane potential and mitochondrial fusion, promoting oxidative phosphorylation in KRASiR LUAD cells. We further found that ΔNp63 is crucial for driving resistance to KRAS G12C inhibitor in vivo using genetically engineered mouse models and patient derived xenografts. Therefore, ΔNp63 is an ideal target to overcome acquired resistance to KRAS inhibitors. Additionally, using atomic force microscopy (AFM), we found that KRASiR cells are stiffer, and that tissue stiffness regulated by YAP/∆Np63 can also result in KRASi resistance. ChIP-seq analysis for ∆Np63 and YAP bound targets are revealing the molecular basis of the mechanisms driving resistance to KRAS G12C inhibitors. Citation Format: Santanu Adhikary, Marco Napoli, Suehelay Acevedo, Christina L. Carr, Jaden R. Baldwin, Nicole Hackel, Hitendra S. Solanki, Yaakov E. Stern, Laxmi Swetha Karanam, Duy T. Nguyen, Eric B. Haura, Elsa R. Flores. Mechanisms regulating resistance to KRAS inhibitor driven by DNp63/YAP regulation of tissue stiffness and metabolic alterations in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5509.