Abstract
Patients with anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) 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. 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. One hundred twenty-six CTC pools and 56 single CTCs were isolated and sequenced. Hotspot regions over 48 cancer-related genes and 14 ALK mutations were examined to identify ALK-independent and ALK-dependent resistance mechanisms. 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, whereas CTC-10 harbored multiple copy-number alterations and whole-genome duplication. 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.
Highlights
Selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have dramatically transformed the therapeutic landscape for patients with ALK-rearranged non–small-cell lung cancer (NSCLC)
The first FDA-approved ALK inhibitor was crizotinib which produced in randomized phase III trials significant improvements in objective response rates and progression-free survival (PFS) compared with chemotherapy, but most patients relapsed within the first year of treatment [1,2,3]
Clinical characteristics Between 2011 and 2017, 17 ALK-rearranged patients had blood sampling for circulating tumor cell (CTC) analysis following radiological progression disease (PD) on ALK-TKI
Summary
Selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have dramatically transformed the therapeutic landscape for patients with ALK-rearranged non–small-cell lung cancer (NSCLC). The first FDA-approved ALK inhibitor was crizotinib which produced in randomized phase III trials significant improvements in objective response rates and progression-free survival (PFS) compared with chemotherapy, but most patients relapsed within the first year of treatment [1,2,3]. Second-generation ALK inhibitors including ceritinib, alectinib, or brigatinib have been approved for patients who progressed on crizotinib, resistance almost always develops [4,5,6,7]. Due to their ability to improve PFS and control brain metastases, these drugs are .
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