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Brief Report: Rapid Acquisition of Alectinib Resistance in ALK-positive Lung Cancer with High Tumor Mutation Burden

INTRODUCTION:

The highly selective ALK inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples.

METHODS:

Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer and who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing (NGS), direct DNA sequencing, and quantitative real-time reverse-transcription polymerase chain reaction.

RESULTS:

ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MET geneamplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs in vivo, whereas the third generation ALK-inhibitor, lorlatinib, diminished tumor growth in vitro and in vivo. NGS indicated high tumor mutation burden (TMB) and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes.

CONCLUSIONS:

High TMB and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy.

Related Products

Cat.No. Product Name Information
S2762 Alectinib Alectinib is a potent ALK inhibitor with IC50 of 1.9 nM in cell-free assays, sensitive to L1196M mutation and higher selectivity for ALK than PF-02341066, NVP-TAE684 and PHA-E429.

Related Targets

ALK