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

• Published in: Cell reports. Medicine 2020-11, Vol.1 (8), p.100131, Article 100131
• Main Authors: Brown, Wells S., McDonald, Paul C., Nemirovsky, Oksana, Awrey, Shannon, Chafe, Shawn C., Schaeffer, David F., Li, Jinyang, Renouf, Daniel J., Stanger, Ben Z., Dedhar, Shoukat
• Format: Article
• Language: English
• Subjects: acquired resistance; AMG 510; Animals; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - genetics; cellular toxicity; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Humans; KRAS; MAP Kinase Signaling System - genetics; Mechanistic Target of Rapamycin Complex 1 - genetics; Mechanistic Target of Rapamycin Complex 2 - genetics; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Mitogen-Activated Protein Kinase Kinases - genetics; Mutation - drug effects; Mutation - genetics; Pancreatic Ducts - drug effects; Pancreatic Neoplasms; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; PDAC; Phosphorylation - drug effects; Phosphorylation - genetics; Protein Kinase Inhibitors - pharmacology; protein translation; Proto-Oncogene Proteins p21(ras) - genetics; signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; tumor regression
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2020.100131

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. [Display omitted] Inhibition of mutant KRAS or MEK leads to adaptive resistance in PDACMutant KRAS or MEK inhibition results in ILK-Rictor-mediated activation of AKTTargeting mutant KRAS or MEK and mTORC1/2 reduces growth and increases cytotoxicityCombination treatment sustains suppression of PDAC tumor progression in mice The majority of pancreatic ductal adenocarcinomas are driven by mutant KRAS, yet targeting the canonical KRAS-MEK pathway has limited clinical impact. Brown et al. identify adaptive resistance mechanisms to mutant KRAS and MEK inhibitors and show that co-targeting mTORC1/2 leads to sustained suppression of tumor progression, revealing effective treatment strategies.