ALK inhibitors against resistance in non-small cell lung cancer: an 18 year medical arms race

Abstract

Anaplastic lymphoma kinase (ALK) inhibitors have transformed the treatment landscape for ALK-positive non-small cell lung cancer (NSCLC) patients. Nonetheless, drug resistance remains a significant challenge. This review presents a timeline-based approach to understanding how drug development has tackled ALK inhibitor resistance, by integrating key historical developments with resistance mechanisms, and evolving treatment strategies; by discussing the discovery of ALK rearrangements, exploring the molecular underpinnings of resistance, and latest advances in combination therapies and fourth-generation inhibitors. By aligning biological and pharmacological milestones with therapeutic progress this review provides a structured overview of how the field has evolved and where future efforts are directed.