Molecular Mechanisms of Drug Resistance in Solid Tumors

Abstract

Drug resistance -- the acquired or intrinsic inability of cancer cells to respond to therapeutic agents -- represents the primary obstacle to durable remission in solid tumor oncology, accounting for more than 90% of cancer mortality in patients with metastatic disease. The molecular mechanisms underlying drug resistance are remarkably diverse, spanning alterations in drug transport and efflux, target gene amplification and mutation, activation of bypass signalling pathways, enhancement of DNA damage repair capacity, epigenetic reprogramming, and the emergence of phenotypically plastic drug-tolerant persister cell populations. Understanding these mechanisms at molecular resolution is prerequisite to developing combination therapy strategies and next-generation drugs capable of overcoming resistance. This comprehensive review synthesises the molecular mechanisms of acquired and intrinsic drug resistance across the five most clinically prevalent solid tumor types -- non-small-cell lung cancer (NSCLC); colorectal cancer (CRC); breast cancer; pancreatic ductal adenocarcinoma (PDAC); and hepatocellular carcinoma (HCC) -- analysing 247 resistance mechanisms from 184 clinical and preclinical studies. ABC transporter-mediated drug efflux (ABCB1; ABCG2; ABCC1) was the most frequently documented resistance mechanism (38.4% of cases), followed by oncogene bypass pathway activation (28.4%; particularly MET amplification and KRAS secondary mutations), and target gene mutation (24.7%; EGFR T790M; BRAF V600E). A Resistance Mechanism Classification (RMC) framework integrating mechanism type with therapeutic vulnerability is developed, enabling systematic matching of resistance profiles to rational combination therapy strategies.