Abstract 4051: STK11-dependent NFkB localization drives characteristic transcriptional signatures in lung cancer

Abstract Lung cancer is responsible for more deaths annually in the U.S. than any other cancer. Despite recent advances in lung cancer detection and treatment, the overall prognosis for patients remains poor since many are diagnosed at an advanced stage where the 5-year survival rate is less than 25%. Immune checkpoint inhibitors (ICI) have dramatically improved outcomes in patients with lung cancer by targeting mechanisms of immune evasion. Unfortunately, only ∼30% of lung adenocarcinomas (LUADs) respond to anti-PD-1 therapy and we cannot reliably identify this group prior to treatment with ICIs. This underscores the need to identify which patients will respond to ICI therapies, while simultaneously highlighting the ∼70% non-responder rate. Recent clinical studies have identified a subgroup of patients with KRAS-driven lung adenocarcinoma (LUAD) who exhibit anti-PD-1 therapy resistance. This group is characterized by tumors with the loss of function (LoF) of Serine/Threonine kinase 11 (STK11). STK11 operates in a heterotrimeric complex with the pseudo-kinase STRADα and the scaffolding protein MO25 where it regulates numerous intracellular signaling networks impacting metabolism, proliferation, transcription, and cell morphology. Why STK11 LoF correlates with anti-PD-1 resistance in the context of KRAS-driven LUAD remains unknown and represents a critical question in lung oncology. We performed whole transcriptome and pathway enrichment studies comparing KRAS-driven/STK11-compentent LUAD cell lines with KRAS-driven/STK11-null lines and identified STK11-loss-dependent differential gene expression profiles consistent with activation of the NF-kappa B (NF-kB) signaling pathway. Based on this analysis, we hypothesize that STK11 LoF leads to constitutive NF-kB-mediated transcriptional activation, including the upregulation of tumor-intrinsic, immune-evasion promoting cytokines, thereby connecting LUAD genotype with a putative mechanism explaining anti-PD1 resistance. Our ongoing studies aim to identify the downstream transcriptional effects of NF-kB activation and reveal the mechanism(s) linked to STK11 activity. To that end, we have established that NF-kB functions downstream of STK11. We demonstrate this relationship using the IKKB inhibitor PS1145. PS1145 blocks IKKB activation leading to NF-kB cytosolic sequestration and rescuing the STK11-loss-dependent transcriptional phenotype. In summary, our work highlights potential interventions to reduce ineffectiveness of immune-checkpoint inhibitor therapy by preventing tumor-intrinsic, genotype-dependent transcriptional changes contributing to immune-evasion. Understanding these molecular mechanisms could inform targeted therapies to overcome resistance and improve survival rates. Citation Format: Allison R. Racela, Sean M. Lenahan, Paula B. Deming, David J. Seward. STK11-dependent NFkB localization drives characteristic transcriptional signatures in lung cancer [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 4051.