부산대학교 도서관

Pancreatic ductal adenocarcinoma (PDA) was responsible for ~ 44,000 deaths in the United States in 2018 and is the epitome of a recalcitrant cancer driven by a pharmacologically intractable oncoprotein, KRAS.sup.1-4. Downstream of KRAS, the RAF[right arrow]MEK[right arrow]ERK signaling pathway plays a central role in pancreatic carcinogenesis.sup.5. However, paradoxically, inhibition of this pathway has provided no clinical benefit to patients with PDA.sup.6. Here we show that inhibition of KRAS[right arrow]RAF[right arrow]MEK[right arrow]ERK signaling elicits autophagy, a process of cellular recycling that protects PDA cells from the cytotoxic effects of KRAS pathway inhibition. Mechanistically, inhibition of MEK1/2 leads to activation of the LKB1[right arrow]AMPK[right arrow]ULK1 signaling axis, a key regulator of autophagy. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic anti-proliferative effects against PDA cell lines in vitro and promotes regression of xenografted patient-derived PDA tumors in mice. The observed effect of combination trametinib plus chloroquine was not restricted to PDA as other tumors, including patient-derived xenografts (PDX) of NRAS-mutated melanoma and BRAF-mutated colorectal cancer displayed similar responses. Finally, treatment of a patient with PDA with the combination of trametinib plus hydroxychloroquine resulted in a partial, but nonetheless striking disease response. These data suggest that this combination therapy may represent a novel strategy to target RAS-driven cancers. Targeted inhibition of RAF-MEK-ERK signaling induces autophagy through the LKB1-AMPK axis, creating a therapeutic vulnerability that can be exploited for treating patients with pancreatic cancer and potentially other RAS-mutant tumors.
Author(s): Conan G. Kinsey [sup.1] [sup.2] , Soledad A. Camolotto [sup.1] , Amelie M. Boespflug [sup.1] [sup.3] [sup.4] , Katrin P. Guillen [sup.1] , Mona Foth [sup.1] , Amanda Truong [...]