학술논문
Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers
Document Type
Article
Author
Kinsey, Conan G.; Camolotto, Soledad A.; Boespflug, Amelie M.; Guillen, Katrin P.; Foth, Mona; Truong, Amanda; Schuman, Sophia S.; Shea, Jill E.; Seipp, Michael T.; Yap, Jeffrey T.; Burrell, Lance D.; Lum, David H.; Whisenant, Jonathan R.; Gilcrease, G. Weldon; Cavalieri, Courtney C.; Rehbein, Kaitrin M.; Cutler, Stephanie L.; Affolter, Kajsa E.; Welm, Alana L.; Welm, Bryan E.; Scaife, Courtney L.; Snyder, Eric L.; McMahon, Martin
Source
Nature Medicine; April 2019, Vol. 25 Issue: 4 p620-627, 8p
Subject
Language
ISSN
10788956; 1546170X
Abstract
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, KRAS1–4. Downstream of KRAS, the RAF→MEK→ERK signaling pathway plays a central role in pancreatic carcinogenesis5. However, paradoxically, inhibition of this pathway has provided no clinical benefit to patients with PDA6. Here we show that inhibition of KRAS→RAF→MEK→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→AMPK→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.