Journal
CELL REPORTS MEDICINE
Volume 1, Issue 8, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.xcrm.2020.100131
Keywords
-
Categories
Funding
- Canadian Cancer Society Research Institute (CCSRI) [703191]
- Canadian Institutes of Health Research (CIHR) [FDN-143318]
- Pancreas Centre BC
- VGH Foundation
- BC Cancer Foundation
Ask authors/readers for more resources
Activating KRAS mutations are found in over 90% of pancreatic ductal adenocarcinomas (PDACs), yet KRAS has remained a difficult target to inhibit pharmacologically. Here, we demonstrate, using several human and mouse models of PDACs, rapid acquisition of tumor resistance in response to targeting KRAS or MEK, associated with integrin-linked kinase (ILK)-mediated increased phosphorylation of the mTORC2 component Rictor, and AKT. Although inhibition of mTORC1/2 results in a compensatory increase in ERK phosphorylation, combinatorial treatment of PDAC cells with either KRAS (G12C) or MEK inhibitors, together with mTORC1/2 inhibitors, results in synergistic cytotoxicity and cell death reflected by inhibition of pERK and pRictor/pAKT and of downstream regulators of protein synthesis and cell survival. Relative to single agents alone, this combination leads to durable inhibition of tumor growth and metastatic progression in vivo and increased survival. We have identified an effective combinatorial treatment strategy using clinically viable inhibitors, which can be applied to PDAC tumors with different KRAS mutations.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available