1. Academic Validation
  2. A multitargeted probe-based strategy to identify signaling vulnerabilities in cancers

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

  • J Biol Chem. 2019 May 24;294(21):8664-8673. doi: 10.1074/jbc.RA118.006805.
Suman Rao 1 Guangyan Du 2 Marc Hafner 3 Kartik Subramanian 3 Peter K Sorger 3 Nathanael S Gray 4
Affiliations

Affiliations

  • 1 Laboratory 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.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
  • 3 Laboratory of Systems Pharmacology, Boston, Massachusetts 02115.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115. Electronic address: Nathanael_Gray@dfci.harvard.edu.
Abstract

Most Cancer cells are dependent on a network of deregulated signaling pathways for survival and are insensitive, or rapidly evolve resistance, to selective inhibitors aimed at a single target. For these reasons, drugs that target more than one protein (polypharmacology) can be clinically advantageous. The discovery of useful polypharmacology remains serendipitous and is challenging to characterize and validate. In this study, we developed a non-genetic strategy for the identification of pathways that drive Cancer cell proliferation and represent exploitable signaling vulnerabilities. Our approach is based on using a multitargeted kinase inhibitor, SM1-71, as a tool compound to identify combinations of targets whose simultaneous inhibition elicits a potent cytotoxic effect. As a proof of concept, we applied this approach to a KRAS-dependent non-small cell lung Cancer (NSCLC) cell line, H23-KRASG12C Using a combination of phenotypic screens, signaling analyses, and kinase inhibitors, we found that dual inhibition of MEK1/2 and insulin-like growth factor 1 receptor (IGF1R)/Insulin Receptor (INSR) is critical for blocking proliferation in cells. Our work supports the value of multitargeted tool compounds with well-validated polypharmacology and target space as tools to discover kinase dependences in Cancer. We propose that the strategy described here is complementary to existing genetics-based approaches, generalizable to other systems, and enabling for future mechanistic and translational studies of polypharmacology in the context of signaling vulnerabilities in cancers.

Keywords

cancer biology; cancer therapy; cell signaling; chemical biology; chemical probe; drug discovery; kinase signaling; multi-targeting; polypharmacology; receptor tyrosine kinase; small molecule.

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