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MAPK pathway inhibition enhances the efficacy of an anti-endothelin B receptor drug conjugate by inducing target expression in melanoma.

Abstract
Therapies targeting the mitogen-activated protein (MAP) kinase pathway in melanoma have produced significant clinical responses; however, duration of response is limited by acquisition of drug resistance. Rational drug combinations may improve outcomes in this setting. We assessed the therapeutic combination of an antibody-drug conjugate (ADC) targeting the endothelin B receptor (EDNRB) with small-molecule inhibitors of the MAP kinase signaling pathway in melanoma. Cell lines and tumor models containing either mutant BRAF or NRAS, or wild-type for both, were exposed to small-molecule inhibitors of BRAF and MEK. Expression of EDNRB was analyzed and the therapeutic impact of combining the anti-EDNRB ADC with the BRAF and MEK inhibitors was assessed. Increased expression of EDNRB in response to inhibition of BRAF and/or MEK was observed and augmented the antitumor activity of the ADC. Enhanced target expression and ADC antitumor activity were realized irrespective of the response of the tumor model to the BRAF or MEK inhibitors alone and could be achieved in melanoma with mutant NRAS, BRAF, or neither mutation. Cells that acquired resistance to BRAF inhibition through long-term culture retained drug-induced elevated levels of EDNRB expression. Expression of EDNRB was not enhanced in normal human melanocytes by inhibition of BRAF and the combination of the ADC with MAPK inhibitors was well-tolerated in mice. The anti-EDNRB ADC combines well with BRAF and MEK inhibitors and could have therapeutic use in the majority of human melanoma cases.
AuthorsJyoti Asundi, Jennifer A Lacap, Suzanna Clark, Michelle Nannini, Leslie Roth, Paul Polakis
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 6 Pg. 1599-610 (Jun 2014) ISSN: 1538-8514 [Electronic] United States
PMID24651527 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright©2014 American Association for Cancer Research.
Chemical References
  • Endothelin B Receptor Antagonists
  • Protein Kinase Inhibitors
  • Receptor, Endothelin B
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Mitogen-Activated Protein Kinase Kinases
Topics
  • Animals
  • Apoptosis (drug effects)
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Endothelin B Receptor Antagonists (administration & dosage)
  • Humans
  • MAP Kinase Signaling System (drug effects)
  • Melanoma (drug therapy, genetics, pathology)
  • Mice
  • Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
  • Protein Kinase Inhibitors (administration & dosage)
  • Proto-Oncogene Proteins B-raf (antagonists & inhibitors)
  • Receptor, Endothelin B (drug effects)
  • Signal Transduction (drug effects)

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