Selective antagonism of anticancer drugs for side-effect removal.
By interfering with signal transduction events that control cell proliferation and fate, kinase inhibitors (KIs) hold promise as anticancer agents. Nevertheless, the functional role of a kinase depends on the cellular context and hence kinase inhibition in off-target cells could lead to side effects. For instance, this context dependence renders many KIs potentially cardiotoxic since inhibition of primary cancer targets such as ABL, RAF1 or AMPK recruits pro-apoptotic pathways in cardiomyocytes. Motivated by these observations, we propose a mode of 'therapeutic editing' where one drug (the editor) suppresses the side effect promoted by the primary drug as it impacts off-target cells. Editor and primary drug have overlapping therapeutic impact, and the editor suppresses the downstream propagation of toxicity-related signaling.
Fernández
Ariel
A
Department of Bioengineering, Rice University, Houston, TX 77005, USA. arifer@rice.edu
Sessel
Sean
S
D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000037:antagonists & inhibitors*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D054715:Cardiotoxins / Q000037:antagonists & inhibitors; D016503:Drug Delivery Systems; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D009928:Organ Specificity; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D054715:Cardiotoxins; D047428:Protein Kinase Inhibitors