Overcoming Resistance to Targeted Anticancer Therapies through Small-Molecule-Mediated MEK Degradation

Jessie Peh, Matthew W. Boudreau, Hannah M. Smith, Paul J. Hergenrother

Research output: Contribution to journalArticle

Abstract

The discovery of mutant or fusion kinases that drive oncogenesis, and the subsequent approval of specific inhibitors for these enzymes, has been instrumental in the management of some cancers. However, acquired resistance remains a significant problem in the clinic, limiting the long-term effectiveness of most of these drugs. Here we demonstrate a general strategy to overcome this resistance through drug-induced MEK cleavage (via direct procaspase-3 activation) combined with targeted kinase inhibition. This combination effect is shown to be general across diverse tumor histologies (melanoma, lung cancer, and leukemia) and driver mutations (mutant BRAF or EGFR, fusion kinases EML4-ALK and BCR-ABL). Caspase-3-mediated degradation of MEK kinases results in sustained pathway inhibition and substantially delayed or eliminated resistance in cancer cells in a manner far superior to combinations with MEK inhibitors. These data suggest the generality of drug-mediated MEK kinase cleavage as a therapeutic strategy to prevent resistance to targeted anticancer therapies. Rapid onset of resistance to targeted kinase inhibitors limits their use in treating advanced cancers. Peh et al. show that combination of diverse kinase inhibitors with a procaspase-3 activating compound (PAC-1) leads to degradation of MEK1/2, dramatically delaying acquired resistance.

Original languageEnglish (US)
Pages (from-to)996-1005.e4
JournalCell chemical biology
Volume25
Issue number8
DOIs
StatePublished - Aug 16 2018

Keywords

  • apoptosis
  • cancer
  • caspase activation
  • kinases
  • resistance
  • targeted therapy

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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