ALK in lung cancer: past, present, and future

Abstract

In 2007, scientists discovered that anaplastic lymphoma kinase (ALK) gene rearrangements are present in a small subset of non-small-cell lung cancers. ALK-positive cancers are highly sensitive to small-molecule ALK kinase inhibitors, such as crizotinib. Phase I and II studies of crizotinib in ALK-positive lung cancer demonstrated impressive activity and clinical benefit, leading to rapid US Food and Drug Administration approval in 2011. Although crizotinib induces remissions and extends the lives of patients, cures are not achieved as resistance to therapy develops. In this review, we will discuss the history of this field, current diagnostic and treatment practices, and future challenges and opportunities to advance outcomes for patients with ALK-positive lung cancers.

Fig 1.

Schematic diagram depicting some of the anaplastic lymphoma kinase (ALK) fusion proteins identified in non–small-cell lung cancer (NSCLC). Echinoderm microtubule-associate protein-like 4 (EML4) –ALK variants are the predominant ALK fusions in NSCLC. More than 20 EML4-ALK variants have been identified, nine of which are shown here. Three other partner proteins have been identified in NSCLC: TFG, KIF5B, and KLC1. Three different KIB5B-ALK variants have been identified (not shown). The blue rectangles within each fusion protein symbolize the ALK tyrosine kinase domain. Adapted.

Fig 2.

Fluorescence in situ hybridization assay for diagnosing anaplastic lymphoma kinase (ALK) rearrangement. In this assay, DNA probes with attached fluorescent dyes (red and green) flank the highly conserved breakpoint within the ALK gene. Separation of the probes because of ALK gene rearrangement results in splitting of the red and green signals (arrows). Reprinted with permission.

Fig 3.

Typical clinical response of an anaplastic lymphoma kinase (ALK) –positive patient to crizotinib. (A) Before crizotinib; (B) after 7 weeks of crizotinib. Reprinted with permission.

Fig 4.

Summary of crizotinib resistance mechanisms in anaplastic lymphoma kinase (ALK) –positive non–small-cell lung cancer. Question marks indicate patients in whom the mechanism of resistance is unknown. EGFR, epidermal growth factor receptor. (*) Patients with more than one resistance mechanism.