Sequential and Dual Inhibition of Pleiotropic Targets in Cancer—A Novel Strategy to Sensitize Tumor Cells to Targeted Therapies and Overcome Resistance

In this paper we discuss the rationale of applying a “sequential” targeted therapy with a specific application in clinical practice, given our understanding of cancer heterogenous and dynamic biology. We explore the advantages of “single inhibition” to combinational therapies and dual inhibition on key pathways, as well as a multi-step approach to use “oncological addiction” and “oncogenic shock” as a suicide plan for cancer. We specifically explain how the downstream targets can be used to “create” feedback loops in an advantage for creating actionable targets in upstream signaling molecules. We apply this hypothesis in the clinical setting, with superior outcomes shown in a series of case studies. We conclude that “sequential and dual inhibition” can be considered a meaningful approach to checkmate the tumor, with minimum chance of tumor resistance. We recommend further clinical studies to generate further hypotheses based on each actionable target.