Reference Detail

Ref Type

Journal Article

PMID

(34058070)

Authors

Sánchez-Herrero E, Serna-Blasco R, Ivanchuk V, García-Campelo R, Dómine Gómez M, Sánchez JM, Massutí B, Reguart N, Camps C, Sanz-Moreno S, Calabuig-Fariñas S, Jantus-Lewintre E, Arnal M, Fernández-Orth D, Calvo V, González-Rumayor V, Provencio M, Romero A

Title

NGS-based liquid biopsy profiling identifies mechanisms of resistance to ALK inhibitors: a step toward personalized NSCLC treatment.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular oncology	15	9	2021 09	2363-2376	Mol Oncol

URL

Abstract Text

Despite impressive and durable responses, nonsmall cell lung cancer (NSCLC) patients treated with anaplastic lymphoma kinase (ALK) inhibitors (ALK-Is) ultimately progress due to development of resistance. Here, we have evaluated the clinical utility of circulating tumor DNA (ctDNA) profiling by next-generation sequencing (NGS) upon disease progression. We collected 26 plasma and two cerebrospinal fluid samples from 24 advanced ALK-positive NSCLC patients at disease progression to an ALK-I. These samples were analyzed by NGS and digital PCR. A tool to retrieve variants at the ALK locus was developed (VALK tool). We identified at least one resistance mutation in the ALK locus in ten (38.5%) plasma samples; the G1269A and G1202R mutations were the most prevalent among patients progressing to first- and second-generation ALK-Is, respectively. Overall, 61 somatic mutations were detected in 14 genes: TP53, ALK, PIK3CA, SMAD4, MAP2K1 (MEK1), FGFR2, FGFR3, BRAF, EGFR, IDH2, MYC, MET, CCND3, and CCND1. Specifically, a deletion in exon 19 in EGFR, a non-V600 BRAF mutation (G466V), and the F129L mutation in MAP2K1 were identified in four patients who showed no objective survival benefit from ALK-Is. Potential ALK-I-resistance mutations were also found in PIK3CA and IDH2. Finally, a c-MYC gain, along with a loss of CCND1 and FGFR3, was detected in a patient progressing on a first-line treatment with crizotinib. We conclude that NGS analysis of liquid biopsies upon disease progression identified different putative ALK-I-resistance mutations in most cases and could be a valuable approach for therapy decision making.

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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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK ALK L1196M	lung adenocarcinoma	predicted - resistant	Crizotinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK L1196M was identified at progression on Xalkori (crizotinib) in a patient with non-small cell lung cancer harboring EML4-ALK (PMID: 34058070).	34058070
EML4 - ALK IDH2 R140Q	lung adenocarcinoma	predicted - resistant	Alectinib	Case Reports/Case Series	Actionable	In a clinical case study, IDH2 R140Q was identified at progression on Alecensa (alectinib) in a patient with non-small cell lung cancer harboring EML4-ALK (PMID: 34058070).	34058070
EML4 - ALK ALK V1180L	lung adenocarcinoma	predicted - resistant	Alectinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK V1180L was identified at progression on Alecensa (alectinib) in a patient with lung adenocarcinoma harboring EML4-ALK (PMID: 34058070).	34058070
EML4 - ALK ALK A1200V	lung adenocarcinoma	predicted - resistant	Crizotinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK A1200V was identified at progression on Xalkori (crizotinib) in a patient with lung adenocarcinoma harboring EML4-ALK (PMID: 34058070).	34058070
EML4 - ALK ALK G1269A	lung adenocarcinoma	predicted - resistant	Crizotinib	Case Reports/Case Series	Actionable	In a clinical case study, ALK G1269A was identified at progression on Xalkori (crizotinib) in two patients with lung adenocarcinoma harboring EML4-ALK (PMID: 34058070).	34058070