Not the comfy chair! Cancer drugs that act against multiple active sites

ABSTRACT

Introduction: Discoveries of novel signal transduction pathways in the 1990s stimulated drug companies to develop small molecule tyrosine kinase and serine / threonine kinase inhibitors which were based on catalytic site inhibition. All kinases bind ATP and catalyze phosphate transfer and, therefore, inhibitors that block ATP binding and its metabolism would be predicted to have a known on-target specificity but were also likely to have many unknown or unrecognized targets due to similarities in all ATP binding pockets. This on-target off-target biology of kinase inhibitors, which exhibit a “signal” in the clinic, means that therapeutically valuable agents are acting through unknown biological processes to mediate their anti-tumor effects.

Areas covered: This perspective discusses drug therapies whose actions cannot be explained by their actions on the original targeted kinase; it concludes with a methodology to screen for changes in cell signaling via in-cell western immunoblotting.

Expert opinion: Most malignancies do not depend on survival signaling from one specific mutated proto-oncogene, especially for previously treated malignancies where multiple clonal variants of the primary tumor have evolved. Hence, the concept of a highly “personalized medicine” approach fails because it is unlikely that a specific therapy will kill all clonal variants of the tumor.

KEYWORDS:

• Autophagy
• apoptosis
• chaperone
• drug
• endoplasmic reticulum
• ERK
• histone deacetylase
• kinase
• MAP kinase
• neratinib
• off-target effect
• pazopanib
• pemetrexed
• receptor tyrosine kinase
• sorafenib
• survival signaling

Article Highlights

• Targeted kinase inhibitors often have additional, unknown or unrecognized targets because of similarities in ATP binding pockets.

• The concept of a highly ‘personalized medicine’ approach to cancer can fail because it is unlikely that a specific therapy will kill all clonal variants of the tumor.

• Analyses of RNA levels can be helpful, but unless protein phosphorylation events are agnostically catalogued, the true biology of many anti-cancer agents cannot be fully understood.

• Multi-channel fluorescence microscopy, via in-cell immunoblotting, represents a state-of-the-art approach to define changes in protein expression, protein phosphorylation, and protein localization in a 96-well plate format.

• The over-emphasis on basic research goals, rather than translational goals leading to new trials, is depriving stakeholders of novel rationally developed drug combinations which would improve progression free and overall survival rates.

This box summarizes key points contained in the article.

Declaration of interest

P Dent has received funding from Genzada Pharmaceuticals and Puma Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

Support for the present study was funded from philanthropic funding from Massey Cancer Center and the Universal Inc. Chair in Signal Transduction Research. P Dent has received funding by the Commonwealth Health Research Board (CHRB) of Virginia and The US National Cancer Institute (R01 CA192613).