Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer

Hayato Mizuta; Koutaroh Okada; Mitsugu Araki; Jun Adachi; Ai Takemoto; Justyna Kutkowska; Kohei Maruyama; Noriko Yanagitani; Tomoko Oh-hara; Kana Watanabe; Keiichi Tamai; Luc Friboulet; Kazuhiro Katayama; Biao Ma; Yoko Sasakura; Yukari Sagae; Mutsuko Kukimoto-Niino; Mikako Shirouzu; Satoshi Takagi; Siro Simizu; Makoto Nishio; Yasushi Okuno; Naoya Fujita; Ryohei Katayama

doi:10.1038/s41467-021-21396-w

Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer

Hayato Mizuta, Koutaroh Okada, Mitsugu Araki, Jun Adachi, Ai Takemoto, Justyna Kutkowska, Kohei Maruyama, Noriko Yanagitani, Tomoko Oh-hara, Kana Watanabe, Keiichi Tamai, Luc Friboulet, Kazuhiro Katayama, Biao Ma, Yoko Sasakura, Yukari Sagae, Mutsuko Kukimoto-Niino, Mikako Shirouzu, Satoshi Takagi, Siro SimizuMakoto Nishio, Yasushi Okuno, Naoya Fujita, Ryohei Katayama

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Abstract

ALK gene rearrangement was observed in 3%–5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI–resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.

Original language	English
Article number	1261
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21396-w
Publication status	Published - 1 Dec 2021

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Mizuta, H., Okada, K., Araki, M., Adachi, J., Takemoto, A., Kutkowska, J., Maruyama, K., Yanagitani, N., Oh-hara, T., Watanabe, K., Tamai, K., Friboulet, L., Katayama, K., Ma, B., Sasakura, Y., Sagae, Y., Kukimoto-Niino, M., Shirouzu, M., Takagi, S., ... Katayama, R. (2021). Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer. Nature Communications, 12(1), Article 1261. https://doi.org/10.1038/s41467-021-21396-w

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title = "Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer",

abstract = "ALK gene rearrangement was observed in 3%–5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI–resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.",

author = "Hayato Mizuta and Koutaroh Okada and Mitsugu Araki and Jun Adachi and Ai Takemoto and Justyna Kutkowska and Kohei Maruyama and Noriko Yanagitani and Tomoko Oh-hara and Kana Watanabe and Keiichi Tamai and Luc Friboulet and Kazuhiro Katayama and Biao Ma and Yoko Sasakura and Yukari Sagae and Mutsuko Kukimoto-Niino and Mikako Shirouzu and Satoshi Takagi and Siro Simizu and Makoto Nishio and Yasushi Okuno and Naoya Fujita and Ryohei Katayama",

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year = "2021",

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doi = "10.1038/s41467-021-21396-w",

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Mizuta, H, Okada, K, Araki, M, Adachi, J, Takemoto, A, Kutkowska, J, Maruyama, K, Yanagitani, N, Oh-hara, T, Watanabe, K, Tamai, K, Friboulet, L, Katayama, K, Ma, B, Sasakura, Y, Sagae, Y, Kukimoto-Niino, M, Shirouzu, M, Takagi, S, Simizu, S, Nishio, M, Okuno, Y, Fujita, N & Katayama, R 2021, 'Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer', Nature Communications, vol. 12, no. 1, 1261. https://doi.org/10.1038/s41467-021-21396-w

TY - JOUR

T1 - Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer

AU - Mizuta, Hayato

AU - Okada, Koutaroh

AU - Araki, Mitsugu

AU - Adachi, Jun

AU - Takemoto, Ai

AU - Kutkowska, Justyna

AU - Maruyama, Kohei

AU - Yanagitani, Noriko

AU - Oh-hara, Tomoko

AU - Watanabe, Kana

AU - Tamai, Keiichi

AU - Friboulet, Luc

AU - Katayama, Kazuhiro

AU - Ma, Biao

AU - Sasakura, Yoko

AU - Sagae, Yukari

AU - Kukimoto-Niino, Mutsuko

AU - Shirouzu, Mikako

AU - Takagi, Satoshi

AU - Simizu, Siro

AU - Nishio, Makoto

AU - Okuno, Yasushi

AU - Fujita, Naoya

AU - Katayama, Ryohei

PY - 2021/12/1

Y1 - 2021/12/1

N2 - ALK gene rearrangement was observed in 3%–5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI–resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.

AB - ALK gene rearrangement was observed in 3%–5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI–resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.

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U2 - 10.1038/s41467-021-21396-w

DO - 10.1038/s41467-021-21396-w

M3 - Article

C2 - 33627640

AN - SCOPUS:85101566967

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1261

ER -

Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer

Abstract

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