Abstract
Introduction: The highly selective ALK receptor tyrosine kinase (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 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, 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 MNNG HOS transforming gene (MET) gene amplification 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. Next-generation sequencing indicated high tumor mutation burden 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 tumor mutation burden 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.
| Original language | English |
|---|---|
| Journal | Journal of Thoracic Oncology |
| DOIs | |
| Publication status | Accepted/In press - Jan 1 2019 |
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Keywords
- Alectinib
- ALK G1202R
- Amphiregulin
- MET
- NSCLC
ASJC Scopus subject areas
- Oncology
- Pulmonary and Respiratory Medicine
Cite this
Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden. / Makimoto, Go; Oohashi, Kadoaki; Tomida, Shuta; Nishii, Kazuya; Matsubara, Takehiro; Kayatani, Hiroe; Higo, Hisao; Ninomiya, Kiichiro; Sato, Akiko; Watanabe, Hiromi; Kano, Hirohisa; Ninomiya, Takashi; Kubo, Toshio; Rai, Kanmei; Ichihara, Eiki; Hotta, Katsuyuki; Tabata, Masahiro; Toyooka, Shinichi; Takata, Minoru; Maeda, Yoshinobu; Kiura, Katsuyuki.
In: Journal of Thoracic Oncology, 01.01.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden
AU - Makimoto, Go
AU - Oohashi, Kadoaki
AU - Tomida, Shuta
AU - Nishii, Kazuya
AU - Matsubara, Takehiro
AU - Kayatani, Hiroe
AU - Higo, Hisao
AU - Ninomiya, Kiichiro
AU - Sato, Akiko
AU - Watanabe, Hiromi
AU - Kano, Hirohisa
AU - Ninomiya, Takashi
AU - Kubo, Toshio
AU - Rai, Kanmei
AU - Ichihara, Eiki
AU - Hotta, Katsuyuki
AU - Tabata, Masahiro
AU - Toyooka, Shinichi
AU - Takata, Minoru
AU - Maeda, Yoshinobu
AU - Kiura, Katsuyuki
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Introduction: The highly selective ALK receptor tyrosine kinase (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 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, 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 MNNG HOS transforming gene (MET) gene amplification 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. Next-generation sequencing indicated high tumor mutation burden 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 tumor mutation burden 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.
AB - Introduction: The highly selective ALK receptor tyrosine kinase (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 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, 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 MNNG HOS transforming gene (MET) gene amplification 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. Next-generation sequencing indicated high tumor mutation burden 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 tumor mutation burden 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.
KW - Alectinib
KW - ALK G1202R
KW - Amphiregulin
KW - MET
KW - NSCLC
UR - http://www.scopus.com/inward/record.url?scp=85071985631&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071985631&partnerID=8YFLogxK
U2 - 10.1016/j.jtho.2019.07.017
DO - 10.1016/j.jtho.2019.07.017
M3 - Article
C2 - 31374369
AN - SCOPUS:85071985631
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
SN - 1556-0864
ER -