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

This is the authors' abstract. We don't add key points for this paper.

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 KRAS Mut -Raf-MEK-c-Myc axis in KRAS Mut lung cancer cells and lung tumors of a spontaneous Kras G12D expression mouse model. KRAS Mut -induced SIRT1 bound to KRAS Mut again and stably deacetylased KRAS Mut lysine 104, which increased KRAS Mut activity. SIRT1 knock down (K/D) or SIRT1 H363Y increased KRAS Mut acetylation, which decreased KRAS Mut activity, which sensitized the anti-cancer effect of cisplatin and erlotinib. Furthermore, Kras G12D/+ ;Sirt1 co/co mice treated with cisplatin and erlotinib robustly reduced tumor burden and increased survival rates compared with these in spontaneous LSL-Kras G12D/+ ;Sirt1 +/+ mice and each drug treatment group. By extension, we found p300 as a KRAS Mut acetyltransferase, which reinforced KRAS Mut lysine 104 acetylation and robustly decreased KRAS Mut activity. KRAS Mut lysine 104 acetylation by p300 and deacetylation by SIRT1 was confirmed by LC-MS/MS. Consistent with this finding, SIRT1 inhibitor, EX527 repressed KRAS Mut acetylation and activity, which abolished synergistically cell proliferation, colony formation, and tumor burden of KRAS Mut combined treatment with cisplatin or erlotinib. Our data reveals a novel pathway critical for the regulation of KRAS Mut lung cancer activity and provides important evidence for the potential application of SIRT1 inhibitor and p300 activator for the combination regimen of KRAS Mut lung cancer patients. Significance KRAS Mut lung cancer activity dependents on acetylation or deacetylation status at lysine 104 by SIRT1 and p300 and could be effective combined regimen to sensitize KRAS Mut NSCLC.