Targeting cancer from a structural biology perspective

Abstract

Cancers result from complex evolutionary processes with selective pressure leading to the accumulation of multiple mutations in proteins involved in the signaling circuitry and basic functions of the cell. Together, the mutant gene products co-opt the cell signaling programs that maintain homeostasis in normal tissues to serve the uncontrolled proliferation, survival, angiogenesis, metabolic, and migration functions that allow cancer cells to thrive at the expense of the organism. The details of how this happens are still not entirely understood. However, intense research in the last two decades has revealed a common set of hallmark traits acquired by cells in the progression to all cancers. A seminal article by Hanahan and Weinberg in 2000 (Hanahan and Weinberg 2000) first identified six hallmarks, with an update a decade later in 2011 (Hanahan and Weinberg 2011) that provided more detailed understanding of the original hallmarks and added two emerging new ones. It also identified enabling characteristics that facilitate acquisition of the hallmarks by cancer cells. In the present chapter, we briefly summarize the hallmarks of cancer and use the Hanahan and Weinberg framework to exemplify targets in signaling pathways that lead to each of the hallmarks from a structural biology perspective. We summarize the current state of inhibitors for at least one major target protein in each of the hallmark signaling circuitry.