ALK: A Driver of Cancer Pathogenesis1

ALK gene rearrangements are the primary drivers of disease in ALK+ NSCLC2

AKT=AKT8 virus oncogene cellular homolog; ALK=anaplastic lymphoma kinase; BAD=bcl-2–associated death promoter protein; EML4=echinoderm microtubule-associated protein-like 4; ERK=extracellular signal-regulated kinase; IP3=inositol trisphosphate; MEK=mitogen-activated protein kinase/ERK kinase; mTOR=mammalian target of rapamycin; NSCLC=non-small cell lung cancer; PI3K=phosphatidylinositol 3-kinase; PIP2=phosphatidylinositol 3,4-bisphosphate; PLC-γ=phospholipase C-γ; Ras=rat sarcoma; S6K=S6 kinase; STAT3/5=signal transducer and activator of transcription 3/5.
 

Adapted by permission from Macmillan Publishers Ltd: Solomon B, Wilner KD, Shaw AT. Current status of targeted therapy for anaplastic lymphoma kinase-rearranged non-small cell lung cancer. Clin Pharmacol Ther. 2014;95:15-23, copyright 2014.

  • In ALK+ non-small cell lung cancer (NSCLC), the ALK gene undergoes a rearrangement, called a translocation, within the chromosome to create a fusion between ALK and another gene2
  • EML4-ALK is the most common ALK fusion in lung cancer, although several other ALK fusions have been reported3
  • ALK gene rearrangements occur in approximately 5% of patients with NSCLC2

ALK fusion proteins are constitutively active, promoting downstream signaling pathways involved in the proliferation and survival of tumor cells3

  • Independent of ligand binding, EML4—or the partner protein—facilitates dimerization of the fusion protein, resulting in the constitutive activation of the ALK kinase domain4
  • At the cellular level, the ALK fusion protein may become the sole regulator of critical downstream signaling pathways, such as the Ras/MAPK, PI3K/AKT, and JAK/STAT pathways2

ALK is an established target in ALK-rearranged NSCLC2,5

  • Tumor cells harboring the ALK rearrangement become dependent on ALK, a key regulator of tumor cell growth and survival5
  • ALK is minimally expressed in normal tissues6

CNS metastasis: A common site of progression in ALK+ NSCLC7

ALK resistance mechanisms

Glossary

References

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