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 KRASMut-Raf-MEK-c-Myc axis in KRASMut lung cancer cells and in lung tumors of a mouse model with spontaneous KrasG12D expression. KRASMut-induced SIRT1 bound to KRASMut and stably deacetylated KRASMut at lysine 104, which increased KRASMut activity. SIRT1 knockdown (K/D) or the SIRT1H363Y mutation increased KRASMut acetylation, which decreased KRASMut activity and sensitized tumors to the anticancer effects of cisplatin and erlotinib. Furthermore, in KrasG12D/+;Sirt1co/co mice, treatment with cisplatin and erlotinib robustly reduced the tumor burden and increased survival rates compared with those in spontaneous LSL-KrasG12D/+;Sirt1+/+ mice and mice in each single-drug treatment group. Then, we identified p300 as a KRASMut acetyltransferase that reinforced KRASMut lysine 104 acetylation and robustly decreased KRASMut activity. KRASMut lysine 104 acetylation by p300 and deacetylation by SIRT1 were confirmed by LC-MS/MS. Consistent with this finding, the SIRT1 inhibitor EX527 suppressed KRASMut activity, which synergistically abolished cell proliferation and colony formation, as well as the tumor burden in KRASMut mice, when combined with cisplatin or erlotinib. Our data reveal a novel pathway critical for the regulation of KRASMut lung cancer progression and provide important evidence for the potential application of SIRT1 inhibitors and p300 activators for the combination treatment of KRASMut lung cancer patients. The interaction between two key proteins in non-small cell lung cancers (NSCLCs) could be targeted to improve the success of chemotherapy. Mutations in the KRAS protein, a regulator of cell growth, are a common driver of NSCLCs, and are associated with poor prognosis. Treating NSCLCs harboring KRAS mutations has proven challenging, and further insights into the mechanisms driving KRAS activity are needed. Using cell cultures and mouse models, Dong Hoon Shin at the National Cancer Center in Goyang-si, South Korea, and co-workers demonstrated that KRAS mutations confer resistance to chemotherapy in NSCLC cells. KRAS mutations increase levels of a protein called SIRT1, and this interaction boosts cancer cell proliferation and tumour growth. Knocking out SIRT1 improved the success of chemotherapy in mouse models. Combined therapies involving SIRT1 inhibitors may therefore improve treatments for NSCLCs.