Abstract B017: Mechanisms regulating resistance to KRAS inhibitors driven by ΔNp63 in lung adenocarcinoma

Abstract Therapies targeting mutant KRAS have been a successful strategy for the treatment of lung adenocarcinoma (LuAD). The major challenges lie when these tumors acquire resistance to these KRAS inhibitors (KRASi). Recent studies have identified various mechanisms via which these tumors become resistant to the drugs, including histological transition from adeno to squamous cell carcinoma. Genetic mutations in TP53 are one of the leading causes of drug resistance. Mutations in TP53 lead to the inhibition of the tumor and metastasis suppressor TAp63 and stabilization of the oncogenic isoform ΔNp63. In PDAC, it is reported that ΔNp63 drives the adeno to squamous transition. We have previously shown that loss of ΔNp63 in a KRAS G12D-driven LuAD leads to fewer tumors and of lower grade. Here we report that cells and tumors resistant to KRAS G12C inhibitors show elevated levels of ΔNp63 compared to the sensitive cells and tumors. We performed a ChIP-seq assay to identify the molecular targets regulated by ΔNp63 in driving resistance to KRASi. We identified genes involved in pathways like drug resistance, metabolism, cell adhesion, KRAS signaling, cellular mechanics, and GPCRs, that are bound by ΔNp63 in KRASiR cells. Interestingly, we also found enrichment of ΔNp63 at the NRF2 promoter in the resistant cells. The KRASiR cells exhibited increased glycolysis, mitochondrial fission, and a lower mitochondrial membrane potential, which reverted upon loss of ΔNp63. We elucidated that ΔNp63 is crucial for driving resistance to the KRAS G12C inhibitor (AMG510, also known as sotorasib) in vivo via adeno to squamous transition. Loss of ΔNp63 induces apoptosis and resensitizes the resistant tumors to AMG510. We also found that ΔNp63 drives resistance to other RAS inhibitors, including the RAS-MULTI-ON inhibitor (RMC6236). We further showed that ΔNp63 is crucial for driving resistance to AMG510 in genetically engineered mouse models, depending on the mutation status of TP53, and in patients treated with sotorasib. Therefore, targeting ΔNp63 can be a novel approach to overcome the acquired resistance to KRAS inhibitors. Citation Format: Santanu Adhikary, Marco Napoli, Suehelay Acevedo Acevedo, Christina L. Carr, Jaden R. Baldwin, Nicole Hackel, Hitendra S. Solanki, Yaakov E. Stern, LaxmiSwetha Karanam, Duy T. Nguyen, Eric B. Haura, Elsa R. Flores. Mechanisms regulating resistance to KRAS inhibitors driven by ΔNp63 in lung adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr B017.