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A multitargeted probe-based strategy to identify signaling vulnerabilities in cancers

Suman Rao1, Guangyan Du2, Marc Hafner3

  • 1Laboratory of Systems Pharmacology, Boston, Massachusetts 02115; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.

The Journal of Biological Chemistry
|March 13, 2019
PubMed

Insights

This study introduces a novel non-genetic method to discover cancer vulnerabilities by using a multitargeted kinase inhibitor. Dual inhibition of MEK1/2 and IGF1R/INSR effectively blocks cancer cell proliferation, highlighting a new strategy for polypharmacology in cancer treatment.

Area of Science:

  • Cancer Biology
  • Pharmacology
  • Molecular Signaling

Background:

  • Cancer cells rely on complex signaling networks for survival, often developing resistance to single-target drugs.
  • Polypharmacology, using drugs that target multiple proteins, offers clinical advantages but is difficult to discover and validate.
  • Identifying exploitable signaling vulnerabilities in cancer requires innovative strategies beyond traditional genetic approaches.

Purpose of the Study:

  • To develop a non-genetic strategy for identifying cancer cell proliferation drivers and exploitable signaling vulnerabilities.
  • To utilize a multitargeted kinase inhibitor (SM1-71) as a tool to discover effective polypharmacology combinations.
  • To validate the approach in a KRAS-dependent non-small cell lung cancer (NSCLC) cell line.

Main Methods:

  • Employed a multitargeted kinase inhibitor, SM1-71, as a tool compound.
  • Utilized phenotypic screens and signaling analyses to identify target combinations.
  • Applied kinase inhibitors to test the efficacy of dual inhibition strategies.

Main Results:

  • Identified dual inhibition of MEK1/2 and insulin-like growth factor 1 receptor (IGF1R)/insulin receptor (INSR) as critical for blocking proliferation in H23-KRASG12C NSCLC cells.
  • Demonstrated the effectiveness of the non-genetic strategy in discovering a specific polypharmacology combination.
  • Validated the utility of SM1-71 as a tool compound for uncovering kinase dependencies.

Conclusions:

  • Multitargeted tool compounds with well-defined polypharmacology are valuable for discovering kinase dependencies in cancer.
  • The described non-genetic strategy is complementary to genetic approaches and generalizable to other cancer systems.
  • This approach enables future mechanistic and translational studies of polypharmacology in cancer signaling vulnerabilities.
Keywords:
cancer biologycancer therapycell signalingchemical biologychemical probedrug discoverykinase signalingmulti-targetingpolypharmacologyreceptor tyrosine kinasesmall molecule

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