A protracted war against cancer drug resistance

Abstract

Currently, even the most effective anti-cancer therapies are often limited by the development of drug resistance and tumor relapse, which is a major challenge facing current cancer research. A deep understanding of the molecular and biochemical bases of drug efficacy that can help predict the clinical drug resistance, coupled with the evolution of systematic genomic and proteomic technologies, have facilitated studies identifying and elucidating the underlying mechanisms. In this review, we focus on several important issues on cancer drug resistance and provide a framework for understanding the common ways by which cancers develop resistance to therapeutic agents. With the increasing arsenal of novel anticancer agents and techniques, there are now unprecedented opportunities to understand and overcome drug resistance. The proteolysis targeting chimera (PROTAC) technology, immunotherapy, nanomedicine, and real-time monitoring of drug response all provide effective approaches for combating drug resistance. In addition to the advancement of therapeutic technologies, the revolution of treatment concept is also of great importance. We can take advantage of the interplay between drug sensitive and resistant subclones for combating cancer. However, there remains a long way to go in the protracted war against cancer drug resistance.

Keywords: Cancer drug resistance; Cancer evolution; Cancer stem cells; Individualized medicine; Yin-Yang balance.

Fig. 1

A schematic of aggressive and moderate therapeutic regimens

Fig. 2

Schematic illustration of the mechanism of MDR

Fig. 3

The development of drug resistance by CSCs

Fig. 4

The advancement of treatment technology promotes the transformation of treatment concept of cancer. With the advent of nanotechnology, theranostics and the establishment of in vitro drug screening, there has been a significant transformation in the concept of cancer treatment from the initial disease-specific treatment with traditional anti-tumor formulations, through site-specific therapy and spatiotemporal therapy, and ultimately to individualized medicine

Fig. 5

Three key issues concerning cancer drug resistance. (1) Do genetic alterations and epigenetic changes all play pivotal roles in the development of cancer drug resistance? (2) Are the resistant cancer cells the pre-existing clones within the primary tumors, or do they emerge as a result of the acquisition of resistance upon drug exposure? (3) Are the resistant cells derived from normal drug-sensitive cancer cells that undergo genetic or epigenetic changes, or do they originate from CSCs that differentiate into resistant phenotypes?

Fig. 6

The delicate “yin-yang balance” between drug sensitive and resistant cells