ALK: a tyrosine kinase target for cancer therapy

Abstract

The anaplastic lymphoma kinase (ALK) gene plays an important physiologic role in the development of the brain and can be oncogenically altered in several malignancies, including non-small-cell lung cancer (NSCLC) and anaplastic large cell lymphomas (ALCL). Most prevalent ALK alterations are chromosomal rearrangements resulting in fusion genes, as seen in ALCL and NSCLC. In other tumors, ALK copy-number gains and activating ALK mutations have been described. Dramatic and often prolonged responses are seen in patients with ALK alterations when treated with ALK inhibitors. Three of these-crizotinib, ceritinib, and alectinib-are now FDA approved for the treatment of metastatic NSCLC positive for ALK fusions. However, the emergence of resistance is universal. Newer ALK inhibitors and other targeting strategies are being developed to counteract the newly emergent mechanism(s) of ALK inhibitor resistance. This review outlines the recent developments in our understanding and treatment of tumors with ALK alterations.

Figure 1.

Anaplastic lymphoma kinase (ALK) signaling: Pathway figure that depicts normal activation of ALK through ligand binding. Receptor phosphorylation stimulates downstream signaling through the PI3K/AKT, MAPK/ERK, and STAT3 pathways. These signaling cascades can contribute to increased cancer cell growth, survival, and metastasis.

Figure 2.

Activating mutations in ALK: COSMIC (tumor only) frequencies of ALK mutations with published literature on functional and/or therapeutic significance. mRNA sequence depicts full reference sequence of ALK (NM_004304) with exon numbers marked. ALK protein sequence (0–1620 amino acids) shows different functional domains (MAM1, LDL, MAM2, Gly-rich, and kinase domain) with starting and ending amino acid numbers (UniProt). COSMIC frequency units (black circles and numbers in parentheses) refer to the number of tumor samples with a particular single-nucleotide variant (SNV) found in COSMIC. The SNVs without the black circles are referenced in literature that is not recorded in COSMIC.