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

Sánchez-Herrero, Estela; Serna-Blasco, Roberto; Ivanchuk, Vadym; García-Campelo, Rosario; Dómine Gómez, Manuel; Sánchez, José M.; Massutí, Bartomeu; Reguart, Noemí; Camps, Carlos; Sanz-Moreno, Sandra; Calabuig-Fariñas, Sílvia; Jantus-Lewintre, Eloisa; Arnal, Magdalena; Fernández-Orth, Dietmar; Calvo, Virginia; González-Rumayor, Víctor; Provencio, Mariano; Romero, Atocha

doi:http://dx.doi.org/10.1002/1878-0261.13033

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

Citation

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. NGS-based liquid biopsy profiling identifies mechanisms of resistance to ALK inhibitors: a step toward personalized NSCLC treatment. Mol Oncol. 2021;15(9):2363-76. DOI: 10.1002/1878-0261.13033

Abstract

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.