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ALK
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Interpretation 311
Tier 2
ALK
Variants
ALK G1202R
Primary Sites
Lung
Tumor Types
Adenocarcinoma
Non-Small Cell Lung Carcinoma
Interpretation

The anaplastic lymphoma kinase (ALK) has emerged as a potentially relevant biomarker and therapeutic target in a variety of solid and hematologic malignancies. It is a receptor tyrosine kinase (RTK) that is known to be activated either by point mutations or by chromosomal translocations. These genetic alterations act as oncogenic drivers, promoting constitutive, ligand-independent activation of this RTK. Approximately 3-7% of non-small cell lung cancers (NSCLC) harbor ALK fusions/rearrangements. ALK fusion oncogenes are transforming both in vitro and in vivo, defining a distinct clinicopathologic subset of NSCLC that are highly sensitive to therapy with ALK-targeted inhibitors. While crizotinib (ALK/MET TKI) is highly active in patients with ALK-positive NSCLC, patients have been shown to invariably develop resistance to this drug. In approximately one-third of resistant cases, tumors can acquire a secondary mutation within the ALK tyrosine kinase domain. ALK G1202R is postulated to be in the solvent-exposed region abutting the crizotinib-binding site, likely diminishing the binding affinity of crizotinib and other ALK inhibitors to the mutant ALK. G1202R has been shown to cause resistance to crizotinib as well as second generation ALK inhibitors (ceritinib, alectinib).

Citations
  1. Ignatius Ou SH, et al. Next-generation sequencing reveals a Novel NSCLC ALK F1174V mutation and confirms ALK G1202R mutation confers high-level resistance to alectinib (CH5424802/RO5424802) in ALK-rearranged NSCLC patients who progressed on crizotinib. J Thorac Oncol 2014;9(4):549-53
  2. Katayama R, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med 2012;4(120):120ra17
  3. Friboulet L, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov 2014;4(6):662-73
Last updated: 2020-07-24 14:53:15 UTC
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