Advancing lung cancer treatment: Understanding the differences between LUAD and LUSC

Lung cancer remains one of the leading causes of cancer-related mortality, with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) representing the most prevalent subtypes of non-small cell lung cancer (NSCLC). Despite their classification under the same umbrella, these two forms of lung cancer exhibit distinct genetic landscapes, therapeutic targets, and treatment responses.

Recent advancements in next-generation gene sequencing have identified key driver genes that differentiate LUAD and LUSC, influencing their respective clinical management approaches. LUAD is frequently associated with mutations in EGFR, KRAS, ALK, and BRAF, while LUSC is more commonly linked to alterations in PIK3CA, FGFR1, and DDR2. These genetic differences dictate the effectiveness of targeted therapies, making it essential to tailor treatment strategies based on specific molecular profiles.

The divergence between LUAD and LUSC extends beyond genetics, affecting chemotherapy regimens, targeted therapies, and immunotherapy outcomes. For instance, pemetrexed-based chemotherapy demonstrates significant efficacy in LUAD patients but lacks substantial benefits in LUSC due to differences in thymidylate synthase expression. Similarly, targeted treatments such as EGFR tyrosine kinase inhibitors (TKIs) have transformed the therapeutic landscape for LUAD, while the absence of widespread targetable mutations in LUSC presents ongoing challenges. However, recent breakthroughs in necitumumab-based therapies have shown promise in improving survival rates for LUSC patients with EGFR overexpression.

Immunotherapy has emerged as a cornerstone in NSCLC treatment, yet the tumor microenvironment varies significantly between LUAD and LUSC, impacting responses to immune checkpoint inhibitors. While PD-L1 expression levels often serve as predictive biomarkers, additional research into the epigenetic regulation of immune responses may pave the way for more effective combination therapies. Emerging targets, including EZH2, BRD4, and NSD3, are under investigation to enhance the efficacy of current treatment regimens.

By highlighting the molecular and clinical distinctions between LUAD and LUSC, this latest review underscores the importance of precision medicine in lung cancer treatment. As research progresses, integrating genomic insights with personalized therapeutic strategies will be instrumental in improving patient outcomes and revolutionizing the fight against lung cancer.

 

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Reference

Yue Shen, Jie-Qi Chen, Xiang-Ping Li, Differences between lung adenocarcinoma and lung squamous cell carcinoma: Driver genes, therapeutic targets, and clinical efficacy, Genes & Diseases, Volume 12, Issue 3, 2025, 101374, https://doi.org/10.1016/j.gendis.2024.101374

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