Oncogenic KRAS mutation confers chemoresistance by upregulating SIRT1 in non-small cell lung cancer

Kirsten rat sarcoma viral oncogene homologue (KRAS) is a frequent oncogenic driver of solid tumors, including non-small cell lung cancer (NSCLC). The treatment and outcomes of KRAS-mutant cancers have not been dramatically revolutionized by direct KRAS-targeted therapies because of the lack of deep binding pockets for specific small molecule inhibitors. Here, we demonstrated that the mRNA and protein levels of the class III histone deacetylase SIRT1 were upregulated by the KRAS(Mut)-Raf-MEK-c-Myc axis in KRAS(Mut) lung cancer cells and in lung tumors of a mouse model with spontaneous Kras(G12D) expression. KRAS(Mut)-induced SIRT1 bound to KRAS(Mut) and stably deacetylated KRAS(Mut) at lysine 104, which increased KRAS(Mut) activity. SIRT1 knockdown (K/D) or the SIRT1(H363Y) mutation increased KRAS(Mut) acetylation, which decreased KRAS(Mut) activity and sensitized tumors to the anticancer effects of cisplatin and erlotinib. Furthermore, in Kras(G12D/+);Sirt1(co/co) mice, treatment with cisplatin and erlotinib robustly reduced the tumor burden and increased survival rates compared with those in spontaneous LSL-Kras(G12D/+);Sirt1(+/+) mice and mice in each single-drug treatment group. Then, we identified p300 as a KRAS(Mut) acetyltransferase that reinforced KRAS(Mut) lysine 104 acetylation and robustly decreased KRAS(Mut) activity. KRAS(Mut) lysine 104 acetylation by p300 and deacetylation by SIRT1 were confirmed by LC‒MS/MS. Consistent with this finding, the SIRT1 inhibitor EX527 suppressed KRAS(Mut) activity, which synergistically abolished cell proliferation and colony formation, as well as the tumor burden in KRAS(Mut) mice, when combined with cisplatin or erlotinib. Our data reveal a novel pathway critical for the regulation of KRAS(Mut) lung cancer progression and provide important evidence for the potential application of SIRT1 inhibitors and p300 activators for the combination treatment of KRAS(Mut) lung cancer patients.