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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.
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 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 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
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 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 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