Abstract 752: Rapid acquired resistance to alectinib in ALK-positive lung cancers with high tumor mutation burden

Abstract

Abstract Background: Alectinib, a highly selective anaplastic lymphoma kinase (ALK) inhibitor, demonstrates an unprecedented effect in ALK-positive lung cancers. However, some tumors quickly develop resistance to alectinib. In this study, we aimed to investigate the mechanism of the rapidly acquired resistance to alectinib using clinical samples. Methods: Autopsied specimens of lung, liver, and renal tumors were obtained from a 51-year-old male patient with advanced ALK-positive lung cancer, who had acquired resistance to alectinib in only three months. Two alectinib-resistant cell lines were established from pleural effusion (ABC-14) or liver tumors (ABC-17). A patient-derived xenograft (PDX) model was also developed from liver tumors. Next-generation sequencing (NGS), direct DNA sequencing, and quantitative real time reverse transcription-PCR were performed. Results: ABC-14 harbored no ALK mutations and showed sensitivity to crizotinib, an ALK/MET inhibitor. It also showed mesenchymal-epithelial transition factor (MET) gene amplification and amphiregulin overexpression. The combination of crizotinib and erlotinib showed beneficial inhibitory effects on cell growth. ABC-17 and PDX tumors harbored ALK G1202R. PDX tumors metastasized to multiple organs in vivo, whereas lorlatinib, the third-generation ALK inhibitor, diminished tumor growth both in vitro and in vivo. NGS demonstrated high tumor mutation burden (TMB) and heterogeneous evolution of the patient tissues. 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 altered codon sequences. Conclusions: High TMB and heterogeneous tumor evolution may have conferred the rapid resistance to alectinib. Timely administration of lorlatinib or combination therapies with an ALK inhibitor and other RTK inhibitors may constitute a potent therapeutic strategy. Financial support: This research was supported by a Grant for Lung Cancer Research (K.O.), provided by the Japan Lung Cancer Society. Citation Format: Kadoaki Ohashi, Go Makimoto, Shuta Tomida, Kazuya Nishii, Shinichi Toyooka, Katsuyuki Kiura. Rapid acquired resistance to alectinib in ALK-positive lung cancers with high tumor mutation burden [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 752.