Oncogenic dependency on STAT3 serine phosphorylation in KRAS mutant lung cancer.

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 (pY ₇₀₅ site) transcription factor. By contrast, an alternate mitochondrial pool of serine phosphorylated (pS ₇₂₇ 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 pS ₇₂₇ -STAT3 deficiency. The proliferative potential of the transformed Kras ^G12D lung epithelium, and mutant KRAS human LAC cells, was significantly reduced upon pS ₇₂₇ -STAT3 deficiency. Notably, we uncover the multifaceted capacity of constitutive pS ₇₂₇ -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 pS ₇₂₇ -STAT3 in mutant KRAS-driven LAC with potential to guide future therapeutic targeting approaches.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)