Unmasking biomarkers in small cell lung cancer: implication for precision oncology

Small cell lung cancer (SCLC) ranks among the most aggressive cancers, posing significant challenges in early diagnosis and treatment with limited therapeutic options. Smoking is one of the major risk factors, which constitutes a substantial proportion of lung cancer cases globally. Despite extensive studies, little progress has been made in treating SCLC, and therefore a striking need for novel therapeutic strategies. Increased genetic and transcriptional heterogeneity has significantly complicated SCLC, including mutations in key regulators such as TP53, RB1, and MYC family genes. Genetic and Transcriptional heterogeneity of SCLC is further exacerbated by the expression of key regulators, including ASCL1, NEUROD1, YAP1, POU2F3, and ATOH1. Because of their unique biological properties, each distinct subtype exhibits a potential specific therapeutic targeting. Biomarkers act as therapeutic guidance in SCLC as they play an important role in early detection, diagnosis, and prognosis. Distinct functional biomarkers, such as genetic, circulating, biochemical, and imaging, provide valuable insights into tumor biology and patient management. Cancer stem cells (CSCs) are an emerging critical challenge in SCLC as they contribute to disease resistance and render the conventional therapies ineffective, leading to tumor recurrence, e.g., CD133, SOX2, and CD44, etc. This in-depth review provides insight into the current understanding of SCLC biology, encompassing its epidemiology, risk factors, genetic features, and molecular subtypes. It also focuses on recent therapeutic insights underlying the promising biomarkers and inhibitors targeting CSCs to overcome drug resistance and improve overall treatment outcomes in SCLC patients.