Format

Send to

Choose Destination
J Biol Chem. 2019 Mar 11. pii: jbc.RA118.006805. doi: 10.1074/jbc.RA118.006805. [Epub ahead of print]

A multi-targeted probe-based strategy to identify signaling vulnerabilities in cancers.

Author information

1
Harvard Medical School, United States.
2
Dana-Farber Cancer Institute, United States.
3
Bioinformatics and Computational Biology, Genentech, United States.
4
Cancer Biology, Dana-Farber Cancer Institute, United States.

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 paper 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 multi-targeted 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 multi-targeted tool compounds with well-validated polypharmacology and target space as tools to discover kinase dependencies in cancer. We propose that the strategy described here is complementary to existing genetic-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

PMID:
30858179
DOI:
10.1074/jbc.RA118.006805
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center