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). Its treatment and outcomes have been dramatically revolutionized by direct targeted therapies because of the lack of deep binding pockets for specific small -molecule inhibitors. Here, we demonstrated that the class III histone deacetylase SIRT1 mRNA and protein levels were upregulated by the KRASMut-Raf-MEK-c-Myc axis in KRASMut lung cancer cells and lung tumors of a spontaneous KrasG12D expression mouse model. KRASMut-induced SIRT1 bound to KRASMut again and stably deacetylased KRASMut lysine 104, which increased KRASMut activity. SIRT1 knock down (K/D) or SIRT1H363Y increased KRASMut acetylation, which decreased KRASMut activity, which sensitized the anti-cancer effect of cisplatin and erlotinib. Furthermore, KrasG12D/+;Sirt1co/co mice treated with cisplatin and erlotinib robustly reduced tumor burden and increased survival rates compared with these in spontaneous LSL-KrasG12D/+;Sirt1+/+ mice and each drug treatment group. By extension, we found p300 as a KRASMut acetyltransferase, which reinforced KRASMut lysine 104 acetylation and robustly decreased KRASMut activity. KRASMut lysine 104 acetylation by p300 and deacetylation by SIRT1 was confirmed by LC-MS/MS. Consistent with this finding, SIRT1 inhibitor, EX527 repressed KRASMut acetylation and activity, which abolished synergistically cell proliferation, colony formation, and tumor burden of KRASMut combined treatment with cisplatin or erlotinib. Our data reveals a novel pathway critical for the regulation of KRASMut lung cancer activity and provides important evidence for the potential application of SIRT1 inhibitor and p300 activator for the combination regimen of KRASMut lung cancer patients. Significance KRASMut lung cancer activity dependents on acetylation or deacetylation status at lysine 104 by SIRT1 and p300 and could be effective combined regimen to sensitize KRASMut NSCLC.