LKB1 Loss Sensitizes Lung Cancer Cells to PRMT5 inhibition by upregulating NNMT

Cancer is a major obstacle to health of modern people, in which lung cancer has a fairly high incidence and mortality rate, according to the results of the WHO IARC agency in 2021. Lung cancer is known for its hard treatment because of its genetic complexity and heterogeneity, especially the KRAS-mutant and LKB1-lost NSCLC. Here we show that LKB1 inactivation upregulates NNMT through SIK1/2-CRTC2 axis, which decreases the ratio of SAM/SAH. Low ratio of SAM/SAH predicts high sensitivity to PRMT5 inhibition in NSCLC independent of MTA abundance, which was previously broadcast negative to PRMT5 activity in MTAP-absent cancer cells. What’s more, PRMT5 inhibition induces senescence in LKB1-mutant NSCLC cells by upregulating P21. Although there has been quite researches on the mechanism of metabolic remodeling of K/L lung cancer, the treatment methods for this type of lung cancer are still relatively limited. So this project attempts to find the unique metabolic remodeling mode of K/L mutant NSCLC and give specific treatment options.