2. Academic Validation
  3. Overcoming Adaptive Resistance to KRAS and MEK Inhibitors by Co-targeting mTORC1/2 Complexes in Pancreatic Cancer

Overcoming Adaptive Resistance to KRAS and MEK Inhibitors by Co-targeting mTORC1/2 Complexes in Pancreatic Cancer

  • Cell Rep Med. 2020 Nov 17;1(8):100131. doi: 10.1016/j.xcrm.2020.100131.
Wells S Brown 1,  Paul C McDonald 1,  Oksana Nemirovsky 1,  Shannon Awrey 1,  Shawn C Chafe 1,  David F Schaeffer 2 3,  Jinyang Li 4,  Daniel J Renouf 5,  Ben Z Stanger 4,  Shoukat Dedhar 1 6
Affiliations

Affiliations

  • 1 Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada.
  • 2 Pancreas Centre BC, Vancouver General Hospital, Vancouver, BC V3Z 1M9, Canada.
  • 3 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
  • 4 Gastroenterology Division, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 5 Medical Oncology, BC Cancer Agency, Vancouver, BC V5Z 4E6, Canada.
  • 6 Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
PMID: 33294856 DOI: 10.1016/j.xcrm.2020.100131
Abstract

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.

Keywords

AMG 510; KRAS; PDAC; acquired resistance; cellular toxicity; protein translation; signal transduction; tumor regression.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-114277
    99.94%, KRAS G12C抑制剂
    Ras
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