Synthetic Lethal Interaction of Combined BCL-XL and MEK Inhibition Promotes Tumor Regressions in KRAS Mutant Cancer Models

Cancer Cell. 2013 Jan 14;23(1):121-8. doi: 10.1016/j.ccr.2012.11.007. Epub 2012 Dec 13.

Abstract

KRAS is the most commonly mutated oncogene, yet no effective targeted therapies exist for KRAS mutant cancers. We developed a pooled shRNA-drug screen strategy to identify genes that, when inhibited, cooperate with MEK inhibitors to effectively treat KRAS mutant cancer cells. The anti-apoptotic BH3 family gene BCL-XL emerged as a top hit through this approach. ABT-263 (navitoclax), a chemical inhibitor that blocks the ability of BCL-XL to bind and inhibit pro-apoptotic proteins, in combination with a MEK inhibitor led to dramatic apoptosis in many KRAS mutant cell lines from different tissue types. This combination caused marked in vivo tumor regressions in KRAS mutant xenografts and in a genetically engineered KRAS-driven lung cancer mouse model, supporting combined BCL-XL/MEK inhibition as a potential therapeutic approach for KRAS mutant cancers.

Publication types

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

MeSH terms

  • Aniline Compounds / pharmacology*
  • Aniline Compounds / therapeutic use
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Benzimidazoles / pharmacology*
  • Benzimidazoles / therapeutic use
  • Drug Screening Assays, Antitumor
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • Mice
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use
  • bcl-X Protein / antagonists & inhibitors*

Substances

  • AZD 6244
  • Aniline Compounds
  • Antineoplastic Agents
  • Benzimidazoles
  • Sulfonamides
  • bcl-X Protein
  • MAP Kinase Kinase Kinases
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • navitoclax