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Acquired Resistance Mutations to ALK-Inhibitors Identified by Single Circulating Tumor Cell Sequencing in ALK-Rearranged Non-Small-Cell Lung Cancer.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Pailler, Emma Faugeroux, Vincent Oulhen, Marianne Mezquita, Laura Laporte, Mélanie Honoré, Aurélie Lécluse, Yann Queffelec, Pauline Ngocamus, M. Nicotra, Claudio Remon, Jordi Lacroix, Ludovic Planchard, David C. Friboulet, Luc Besse, Benjamin Farace, Françoise |
| Copyright Year | 2019 |
| Abstract | PURPOSE Anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) patients inevitably develop resistance to ALK-inhibitors. New diagnostic strategies are needed to assess resistance mechanisms and provide patients with the most effective therapy. We asked whether single-circulating tumor cell (CTC) sequencing can inform on resistance mutations to ALK-inhibitors and underlying tumor heterogeneity in ALK-rearranged NSCLC. EXPERIMENTAL DESIGN Resistance mutations were investigated in CTCs isolated at the single-cell level from patients at disease progression on crizotinib (n=14) or lorlatinib (n=3). Three strategies including filter laser-capture microdissection, fluorescence activated cell-sorting and the DEPArray were used. 126 CTC-pools and 56 single-CTCs were isolated and sequenced. Hotspots regions over 48 cancer-related genes and 14 ALK mutations were examined to identify ALK-independent and ALK-dependent resistance mechanisms. RESULTS Multiple mutations in various genes in ALK-independent pathways were predominantly identified in CTCs of crizotinib-resistant patients. The RTK-KRAS (EGFR, KRAS, BRAF genes) and TP53 pathways were recurrently mutated. In one lorlatinib-resistant patient, two single-CTCs out of 12 harbored ALK compound-mutations. CTC-1 harbored the ALK G1202R/F1174C compound-mutation virtually similar to ALK G1202R/F1174L present in the corresponding tumor biopsy. CTC-10 harbored a second ALK G1202R/T1151M compound-mutation not detected in the tumor biopsy. By copy-number analysis, CTC-1 and the tumor biopsy had similar profiles while CTC-10 harbored multiple copy-number alterations and whole-genome duplication. CONCLUSIONS Our results highlight the genetic heterogeneity and clinical utility of CTCs to identify therapeutic resistance mutations in ALK-rearranged patients. Single-CTC sequencing may be a unique tool to assess heterogeneous resistance mechanisms and help clinicians for treatment personalization and resistance options to ALK-targeted therapies. |
| File Format | PDF HTM / HTML |
| DOI | 10.1158/1078-0432.CCR-19-1176 |
| PubMed reference number | 31439588 |
| Journal | Medline |
| Alternate Webpage(s) | https://www.rarecells.com/wp-content/uploads/2019/12/201910-Pailler-ClinCanRes.pdf |
| Alternate Webpage(s) | https://doi.org/10.1158/1078-0432.CCR-19-1176 |
| Journal | Clinical cancer research : an official journal of the American Association for Cancer Research |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
