ALK Inhibitors and Non-Small Cell Lung Cancer: A Promising Advance in Targeted Therapy

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ALK Inhibitors and Non-Small Cell Lung Cancer: A Promising Advance in Targeted Therapy
ALK Inhibitors and Non-Small Cell Lung Cancer: A Promising Advance in Targeted Therapy

Despite advances in treatment, lung cancer remains the leading cause of cancer death worldwide and in the United States, with an alarming death/case ratio of 0.86. Of the 1.6 million new cases of lung cancer diagnosed annually (226,160 in the US alone), roughly eight in 10 are non-small cell lung cancer (NSCLC).1-3 Within NSCLC, identification of subsets of patients with specific mutations has led to development of effective targeted therapies.

In 2007, a specific rearrangement of the anaplastic lymphoma kinase (ALK) gene was identified that both initiates and maintains tumor growth in some patients with NSCLC.3,4 ALK rearrangements also are implicated in a number of rare cancers, esophageal squamous cell carcinoma, renal medullary carcinoma, and myeloid leukemia.1,5 NSCLC patients with ALK rearrangements are resistant to therapies that target the epidermal growth factor receptor (EGFR).6 The kinase encoded by ALK presents an attractive anticancer target because it is altered in a number of cancer types, crucial to tumor development, barely expressed in adults, and can be blocked with a designed inhibitor. Patients with ALK rearrangements comprise about 5% of individuals with NSCLC worldwide, representing approximately 70,000 new patients who could benefit from ALK inhibition.1,5,7

ALK Rearrangement in Tumorigenesis

ALK encodes a transmembrane receptor tyrosine kinase belonging to the insulin receptor family. It is not generally expressed in adults but is heavily involved in fetal development.1,5 In NSCLC, the ALK rearrangement involves a chromosomal translocation within EML4 (echinoderm microtubule associated protein-like 4) and fusion with ALK. The rearranged gene expresses a fusion oncoprotein—EML4-ALK—that contains the N-terminal portion of EML-4 and the entire intracellular portion of ALK. Several variants of this oncoprotein have been identified in NSCLC.4,5,8-10

Since ALK kinase activity remains a necessary part of EML4-ALK tumorigenesis, it was hypothesized that an inhibitor designed to block ALK activity would have therapeutic potential in patients harboring the mutation.5

Clinicopathologic Profile of ALK-positive NSCLC

Patients with ALK-positive NSCLC exhibit a clinical profile similar to that of patients harboring EGFR mutations, with minor differences. Compared with other NSCLC populations, ALK-positive patients tend to be younger and to be never-smokers or former light smokers. Where women predominate in EGFR-positive NSCLC, no gender difference has emerged for ALK-positive disease. Almost all ALK-positive lung cancer is adenocarcinoma, with a signet-ring cell type predominating in Western populations and an acinar type predominating in Asian populations.3,7,8,10,12 Patients generally have poorly differentiated tumors and present at later stages.3,12 When compared to patients with EGFR-positive or wild-type NSCLC, ALK-positive patients have a lower response rate to platinum-based chemotherapy and worse survival with standard chemotherapy.12

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