RT Journal Article
SR Electronic
T1 Targeting glucose metabolism sensitizes pancreatic cancer to MEK inhibition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.09.425923
DO 10.1101/2021.01.09.425923
A1 Liang Yan
A1 Bo Tu
A1 Jun Yao
A1 Jing Gong
A1 Alessandro Carugo
A1 Christopher A. Bristow
A1 Qiuyun Wang
A1 Cihui Zhu
A1 Bingbing Dai
A1 Ya’an Kang
A1 Leng Han
A1 Ningping Feng
A1 Yanqing Jin
A1 Jason Fleming
A1 Timothy P. Heffernan
A1 Wantong Yao
A1 Haoqiang Ying
YR 2021
UL http://biorxiv.org/content/early/2021/01/11/2021.01.09.425923.abstract
AB Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal. A critical unmet need exists to explore essential susceptibilities in PDAC and identify druggable targets for tumor maintenance. This is especially challenging in the context of PDAC, in which activating mutations of KRAS oncogene (KRAS*) dominate the genetic landscape. By using an inducible KrasG12D-driven p53 deficient PDAC mouse model (iKras model), we demonstrate that RAF-MEK-MAPK signaling is the major effector for oncogenic Kras-mediated tumor maintenance. However, MEK inhibition has minimal therapeutic effect as single agent for PDAC both in vitro and in vivo. Although MEK inhibition partially downregulates the transcription of glycolysis genes, it surprisingly fails to suppress the glycolysis flux in PDAC cell, which is a major metabolism effector of oncogenic KRAS. Accordingly, In vivo genetic screen identified multiple glycolysis genes as potential targets that may sensitize tumor cells to MAPK inhibition. Furthermore, inhibition of glucose metabolism with low dose 2-deoxyglucose (2DG) in combination with MEK inhibitor dramatically induces apoptosis in KrasG12D-driven PDAC cell in vitro, inhibits xenograft tumor growth and prolongs the overall survival of genetically engineered mouse PDAC model. Molecular and metabolism analyses indicate that co-targeting glycolysis and MAPK signaling results in apoptosis via induction of lethal ER stress. Together, our work suggests that combinatory inhibition of glycolysis and MAPK pathway may serve as an alternative approach to target KRAS-driven PDAC.Competing Interest StatementThe authors have declared no competing interest.