Recent progresses in cancer multidrug resistance and therapeutic options associated with protein damage response

Multidrug resistance (MDR) is a frequent and leading cause of treatment failure and patient mortality in cancer. While numerous biological processes contribute to drug resistance, recent studies have revealed that most anticancer drugs rapidly bind to and damage newly synthesized proteins upon entering cells. This process, termed acute drug protein damage (ADPD), occurs before the drugs act on their canonical targets. To evade the lethal effects of ADPD, cancer cells rapidly initiate a series of protective responses collectively termed the protein damage response (PDR). This cascade includes damage recognition via protein ubiquitination, damage clearance through the proteasome system, and subsequent mitophagy to remove damaged mitochondria caused by the co-import of drugs and damaged proteins. Here, we review the current understanding of multiple biological processes underlying drug resistance, with a focus on the mechanisms of ADPD induced by anticancer drugs, the pivotal role of PDR in driving MDR, and its potential applications in predicting and overcoming drug resistance.