Targeting TGF-β-Smad2/3-JNK1-mediated SIRT1 activity overcomes the chemoresistance of KRAS mutation lung cancer.

Patients with lung cancer harboring a KRAS oncogenic driver mutation have a very poor prognosis. Recently, we reported that SIRT1 is upregulated by the KRAS(Mut)-c-Myc axis, and that KRAS(Mut)-induced SIRT1 is stably deacetylated at lysine 104, which in turn increases KRAS(Mut) activity and enhances chemoresistance. Notably, SIRT1 activity as well as SIRT1 levels are more elevated in KRAS(Mut) cells compared with EGFR(Mut), KRAS(Mut)- and EGFR(Mut)-negative cells, and nontumorigenic cells. This prompted us to investigate the mechanism by which SIRT1 activity was increased and the role of pSIRT1 in the chemoresistance of KRAS(Mut) lung cancer cells. The activated MEK-ERK pathway under KRAS(Mut) increased AP-1 transcription activity, which in turn enhanced TGF-β1 secretion. The secreted TGF-β1 activated the Smad2/3-JNK1 signaling pathway in an autocrine manner, increasing pSIRT1(S27) and pSIRT1(S47), ultimately enhancing KRAS(Mut) activity through KRAS deacetylation and affecting chemoresistance. We identified a small molecule from the natural compound library-Kuwanon C (KWN-C), a SIRT1 activity inhibitor-which reduced pSIRT1(S27) and pSIRT1(S47) levels via a decrease in the activity of the TGF-β1--Smad2/3-JNK1 signaling pathway. Treatment with the SIRT1 activity inhibitor triggered the anticancer effects of cisplatin and pemetrexed in human lung cancer cells, lung orthotopic tumors and a spontaneous in vivo model of KRAS(Mut) lung cancer. Our findings reveal a novel pathway critical for the regulation of SIRT1 activity in KRAS(Mut) lung cancer and provide important evidence for the potential application of SIRT1 activity inhibitors as an adjuvant chemotherapy, overcoming chemoresistance in patients with KRAS(Mut) lung cancer.