Molecularly Targeted Therapy: Great Progress or Evil Cycle

Abstract

Therapeutic mode of cancer patients have shifted during a past few decades from the administration of broadly effective conventional anticancer agents towards the more-specific therapies in individual case and each cancer. This strategy derived from the notion that cancer cells usually become more dependent on and addicted to the activity of a specific molecule which in most cases, is an oncogene product. Along with the prevalence of this concept “oncogene addiction”, this novel and specific therapy called “tailored targeted therapy” came true for each patient [1,2]. The rationale of targeting the molecule selectively overexpressed or activated in cancer cells is that cytotoxicity will be selective/specific for cancer cells, minimizing potential adverse events (AEs). Therefore, effective tailored targeted therapy requires the initial and essential effort to identify the key molecule(s) by which downstream pathways are activated. The representative target molecule has been protein kinase, and thus, receptor tyrosine kinases and the downstream effectors (phosphoinositide-3 kinases [PI3-K], Ras and Raf, etc.) have been attractive therapeutic targets. The highly conserved ATP–binding site within the catalytic domain of most kinases was initially viewed as an appropriate target for the development of selective small-molecule kinase inhibitors. Later, the non-ATP-competitive kinase inhibitors were found to show the higher selectivity without affecting other protein kinases. Eventually, this trial spurred the development of more than 500 molecularly targeted pharmacological agents and about 150 kinase-targeted drugs, and ushered in an era of “molecularly targeted therapy” (MTT) [3].