Abstract 3026: STK11 negatively regulates NFKB signaling in KRAS-driven lung adenocarcinoma
Authors: Seward David Joseph , Lenahan Sean , Racela Allison , Odekunle Israel 
Published: March 2024

In the US, more people die each year from lung cancer than breast, colorectal, and prostate cancers combined. Despite advances in lung cancer detection and treatment, the overall prognosis for patients remains poor. Patients whose lung tumors harbor druggable mutations often experience initial responses with targeted therapies, but acquisition of therapy resistance results in 5-year survival rates that have remained near ~20%. Immune check-point inhibitors (ICI) promise to improve outcomes in patients with lung cancer by targeting mechanisms of immune evasion. Drugs that disrupt PD-L1-mediated immune evasion, including pembrolizumab and nivolumab, have revolutionized treatment for some cancers. Unfortunately, only ~30% of lung adenocarcinomas (LUADs) respond to anti-PD-1 therapy and we cannot reliably identify this group prior to treatment. This underscores the need to discriminate which patients will respond to ICI therapies, while simultaneously highlighting the ~70% non-responder rate. To that end, recent clinical studies have linked anti-PD-1 therapy resistance with Serine/Threonine Kinase 11 (STK11) loss of function (LoF). 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. As an initial approach to understand this phenomenon, we knocked-out STK11 in multiple KRAS-driven, STK11-competent human LUAD cell lines and performed whole transcriptome analyses to identify STK11-loss-dependent differential gene expression profiles. We assert the transcriptional mediators downstream of STK11 governing the changes we report represent therapeutic targets whose antagonism may restore anti-PD-1 efficacy. Supporting this rationale, our data has identified STK11-loss-dependent activation of the NFκ-B transcriptional network. NFκB is a master transcription factor that regulates numerous cytokines, but whether and/or how STK11 directs NFκB activity remains largely unaddressed. We highlight NFκB activation as a potential mechanistic link between STK11 loss and tumor-intrinsic cytokine upregulation. We speculate that STK11 normally acts as a key player in the negative feedback loop limiting NFκB activity. When STK11 is lost, that activity continues unabated. In summary, we propose STK11 loss drives anti-PD-1 therapy resistance by generating an altered tumor immune microenvironment via constitutive activation of NFκB-mediated cytokine production. In future we intend to assess strategies for reversing anti-PD-1 therapy resistance via disruption of the NFκB transcriptional axis in KRAS-driven LUAD lacking STK11.

Citation Format: David Joseph Seward, Sean Lenahan, Allison Racela, Israel Odekunle. STK11 negatively regulates NFKB signaling in KRAS-driven lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3026.