Reference Detail

Ref Type

Journal Article

PMID

(27565911)

Authors

Johnson AC, Dô P, Richard N, Dubos C, Michels JJ, Bonneau J, Gervais R

Title

Identification of I1171N resistance mutation in ALK-positive non-small-cell lung cancer tumor sample and circulating tumor DNA.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Lung cancer (Amsterdam, Netherlands)	99		2016 Sep	38-40	Lung Cancer

URL

Abstract Text

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is sensitive to ALK inhibitor therapy, but resistance invariably develops and can be mediated by certain secondary mutations. The detection of these mutations is useful to guide treatment decisions, but tumors are not always easily accessible to re-biopsy. We report the case of a patient with ALK-rearranged NSCLC who presented acquired resistance to crizotinib and then alectinib. Sequencing analyses of DNA from a liver metastasis biopsy sample and circulating tumor DNA both found the same I1171N ALK kinase domain mutation, known to confer resistance to certain ALK inhibitors. However, the patient then received ceritinib, a 2nd generation ALK inhibitor, and achieved another partial response. This case underlines how ALK resistance mutation detection in peripheral blood could be a reliable, safer, and less invasive alternative to tissue-based samples in NSCLC.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
ALK	I1171N	missense	gain of function	ALK I1171N lies within the protein kinase domain of the Alk protein (UniProt.org). I1171N results in increased ligand-independent Alk phosphorylation and activation of the Stat pathway in culture (PMID: 23239810, PMID: 21838707), activation in in vitro assays (PMID: 33674381, PMID: 25517749), is transforming in cell culture (PMID: 23239810, (PMID: 33674381, PMID: 25517749), and has been demonstrated to occur as a secondary resistance mutation in the context of ALK fusions (PMID: 27565911).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ALK rearrange ALK I1171N	lung non-small cell carcinoma	predicted - resistant	Alectinib	Case Reports/Case Series	Actionable	In a clinical case study, a de novo ALK I1171N mutation was identified in the liver metastasis site and circulating DNA of a non-small cell lung cancer patient harboring an ALK rearrangement after disease progression on Alecensa (alectinib) treatment (PMID: 27565911).	27565911