ALK: A Specific Oncogenic Driver
ALK gene rearrangements are the primary drivers of disease in ALK+ NSCLC1-3
- In ALK+ NSCLC, the ALK gene undergoes a rearrangement, called a translocation, within the chromosome to create a fusion between ALK and another gene1
Adapted from Soda M, Choi YL, Enomoto M, et al. Nature. 2007.
- 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 NSCLC1
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 domain1,4
- 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 pathways1
ALK activates downstream signaling events important in tumorigenesis
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.
ALK is an established target in ALK-rearranged NSCLC1,5
- 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
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; JAK=Janus-family tyrosine kinase; MAPK=mitogen-activated protein kinase; MEK=MAPK/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.
- 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. PMID: 24091716
- Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561-566. PMID: 17625570
- Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol. 2013;31:1105-1111. PMID: 23401436
- Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131:1190-1203. PMID: 18083107
- Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4:120ra17. doi:10.1126/scitranslmed.3003316. PMID: 22277784
- Sakamoto H, Tsukaguchi T, Hiroshima S, et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011;19:679-690. PMID: 21575866