Oncogenic dependency on STAT3 serine phosphorylation in KRAS mutant lung cancer

Abstract

The oncogenic potential of the latent transcription factor signal transducer and activator of transcription (STAT)3 in many human cancers, including lung cancer, has been largely attributed to its nuclear activity as a tyrosine-phosphorylated (pY₇₀₅ site) transcription factor. By contrast, an alternate mitochondrial pool of serine phosphorylated (pS₇₂₇ site) STAT3 has been shown to promote tumourigenesis by regulating metabolic processes, although this has been reported in only a restricted number of mutant RAS-addicted neoplasms. Therefore, the involvement of STAT3 serine phosphorylation in the pathogenesis of most cancer types, including mutant KRAS lung adenocarcinoma (LAC), is unknown. Here, we demonstrate that LAC is suppressed in oncogenic Kras^G12D-driven mouse models engineered for pS₇₂₇-STAT3 deficiency. The proliferative potential of the transformed Kras^G12D lung epithelium, and mutant KRAS human LAC cells, was significantly reduced upon pS₇₂₇-STAT3 deficiency. Notably, we uncover the multifaceted capacity of constitutive pS₇₂₇-STAT3 to metabolically reprogramme LAC cells towards a hyper-proliferative state by regulating nuclear and mitochondrial (mt) gene transcription, the latter via the mtDNA transcription factor, TFAM. Collectively, our findings reveal an obligate requirement for the transcriptional activity of pS₇₂₇-STAT3 in mutant KRAS-driven LAC with potential to guide future therapeutic targeting approaches.