A receptor tyrosine kinase ROR1 inhibitor (KAN0439834) induced significant apoptosis of pancreatic cells which was enhanced by erlotinib and ibrutinib

PLoS One. 2018 Jun 1;13(6):e0198038. doi: 10.1371/journal.pone.0198038. eCollection 2018.

Abstract

There is a great unmet medical need in pancreatic carcinoma (PC) for novel drugs with other mechanisms of action than existing. PC cells express the onco-fetal RTK ROR1, absent on most normal post-partem cells. ROR1 is involved in proliferation, survival, EMT and metastasis of tumor cells in various malignancies. A small molecule inhibitor (KAN0439834) (530 Da) targeting the TK domain of ROR1 was developed and the activity in ROR1 expressing human PC cell lines (n = 8) evaluated. The effects were compared to a murine mAb against the external part of ROR1, gemcitabine, erlotinib and ibrutinib. KAN0439834 induced significant apoptosis of the tumor cells. EC50 values for KAN0439834 varied between 250-650 nM depending on the cell line. The corresponding values for erlotinib and ibrutinib were 10-40 folds higher. KAN0439834 was much more effective in inducing tumor cell death than the ROR1 mAb although both inhibited ROR1 phosphorylation and downstream non-canonical Wnt pathway molecules. Combination of KAN0439834 with erlotinib or ibrutinib had significant additive effects on tumor cell death. A first-in-class small molecule ROR1 inhibitor (KAN0439834) showed promising in vitro activity against a number of human PC cell lines. Interesting is the additive effects of erlotinib and ibrutinib which warrants further studies as both these agents are in clinical trials for pancreatic carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Drug Synergism
  • Erlotinib Hydrochloride / pharmacology*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-6 / chemistry
  • Organic Chemicals / pharmacology*
  • Pancreas / drug effects
  • Pancreas / pathology*
  • Pancreatic Neoplasms / pathology
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Multimerization / drug effects
  • Protein Structure, Quaternary
  • Pyrazoles / pharmacology*
  • Pyrimidines / pharmacology*
  • Receptor Tyrosine Kinase-like Orphan Receptors / antagonists & inhibitors*
  • Receptor Tyrosine Kinase-like Orphan Receptors / chemistry
  • Receptor Tyrosine Kinase-like Orphan Receptors / metabolism

Substances

  • Antineoplastic Agents
  • KAN0439834
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Organic Chemicals
  • PCI 32765
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Erlotinib Hydrochloride
  • Receptor Tyrosine Kinase-like Orphan Receptors

Grant support

This study was supported by grants from: the Swedish Research Council (HM, Proj nr: K2013-64X-21464-04-3), https://www.vr.se/; The Cancer and Allergy Foundation (HM, Ref No.: 150 420 and 150 122), https://cancerochallergifonden.se; The Cancer Society in Stockholm (HM, Ref No.: 144142, 164122; AÖ, Ref No.: 151313), www.rahfo.se; The King Gustaf V Jubilee Fund (AÖ, Ref nr: 144193), www.rahfo.se/; The Swedish Cancer Society (AÖ, 14 0395, 15 0894, 160534), www.cancerfonden.se; The Torsten Söderbergs Foundation (HM), www.torstensoderbergsstiftelse.se; AFA Insurance (AÖ, Ref nr: 130054), www.afaforsakring.se; The Karolinska Institutet Foundation (HM, MHF, AÖ), www.ki.se; The Stockholm County Council (AÖ, Ref No.: 20150070), https://forskningsstod.vmi.se/Ansokan/start.asp; The Felix Mindus Foundation (HM), www.ki.se; Vinnova (AÖ, Ref nr: 2015-01219), www.vinnova.se. AHD, MHF, AM, JS, JV, SB, EO, TO, AÖ and HM are shareholders of Kancera AB. AM, JS, JV, SB, EO, and TO are employees of Kancera AB. HM has received research grants from Kancera. The specific roles of these authors are articulated in the Author Contributions section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.