Mcl-1 Degradation Is Required for Targeted Therapeutics to Eradicate Colon Cancer Cells

Cancer Res. 2017 May 1;77(9):2512-2521. doi: 10.1158/0008-5472.CAN-16-3242. Epub 2017 Feb 15.


The Bcl-2 family protein Mcl-1 is often degraded in cancer cells subjected to effective therapeutic treatment, and defective Mcl-1 degradation has been associated with intrinsic and acquired drug resistance. However, a causal relationship between Mcl-1 degradation and anticancer drug responses has not been directly established, especially in solid tumor cells where Mcl-1 inhibition alone is insufficient to trigger cell death. In this study, we present evidence that Mcl-1 participates directly in determining effective therapeutic responses in colon cancer cells. In this setting, Mcl-1 degradation was induced by a variety of multikinase inhibitor drugs, where it relied upon GSK3β phosphorylation and FBW7-dependent ubiquitination. Specific blockade by genetic knock-in (KI) abolished apoptotic responses and conferred resistance to kinase inhibitors. Mcl-1-KI also suppressed the antiangiogenic and anti-hypoxic effects of kinase inhibitors in the tumor microenvironment. Interestingly, these same inhibitors also induced the BH3-only Bcl-2 family protein PUMA, which is required for apoptosis. Degradation-resistant Mcl-1 bound and sequestered PUMA from other prosurvival proteins to maintain cell survival, which was abolished by small-molecule Mcl-1 inhibitors. Our findings establish a pivotal role for Mcl-1 degradation in the response of colon cancer cells to targeted therapeutics, and they provide a useful rational platform to develop Mcl-1-targeting agents that can overcome drug resistance. Cancer Res; 77(9); 2512-21. ©2017 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Line, Tumor
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • Drug Resistance, Neoplasm / genetics*
  • F-Box Proteins / genetics
  • F-Box-WD Repeat-Containing Protein 7
  • Gene Knock-In Techniques
  • Glycogen Synthase Kinase 3 beta / genetics
  • Humans
  • Mice
  • Molecular Targeted Therapy*
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics*
  • Phosphorylation
  • Protein Kinase Inhibitors / administration & dosage
  • Proteolysis / drug effects
  • Ubiquitin-Protein Ligases / genetics
  • Xenograft Model Antitumor Assays


  • Cell Cycle Proteins
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Protein Kinase Inhibitors
  • Ubiquitin-Protein Ligases
  • Glycogen Synthase Kinase 3 beta