Author(s):
Soma Garani and Ahana Chakraborty

Abstract:
Lung cancer is a leading cause of mortality worldwide, accounting for approximately 18% of global cancer deaths and representing a significant public health burden, particularly in countries with high smoking rates and pollution. This review examines the critical role of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC) and explores how ALK mutagenesis analysis is a therapeutic strategy for this malignancy. ALK gene rearrangements, occurring in 3–7% of NSCLC cases, most commonly result in the EML4-ALK fusion protein, which drives uncontrolled cancer cell proliferation through constitutive activation of downstream signaling pathways including PI3K/AKT, RAS/MAPK, JAK/STAT, and PLCγ. The discovery of these molecular alterations has revolutionized lung cancer treatment, enabling the development of targeted ALK inhibitors ranging from first-generation drugs like crizotinib to advanced third-generation inhibitors such as lorlatinib. However, acquired resistance through secondary ALK mutations and bypass signalling pathways remains a significant clinical challenge. This study focuses on ALK protein mutagenesis analysis as a cornerstone of precision oncology. By systematically characterizing resistance mutations such as L1196M, G1269A, F1174L, and G1202R, we can predict treatment failure, guide therapeutic selection, and design next-generation inhibitors with improved efficacy. Through techniques such as site-directed mutagenesis, CRISPR-Cas9 gene editing, and structure-based drug design supported by crystallographic studies, researchers are developing more potent compounds tailored to mutant ALK protein conformations. Our research aims to advance personalized medicine by integrating molecular diagnostics, real-time mutation monitoring, and adaptive treatment strategies. Understanding the complex interplay between ALK mutagenesis and therapeutic response will enable clinicians to overcome resistance mechanisms, optimize combination therapies, and ultimately improve survival outcomes for ALK-positive lung cancer patient. This approach represents a critical step toward transforming lung cancer from a uniformly fatal disease to a manageable chronic condition through precision-targeted interventions.

Pages: 855-872

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