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<scp>Yes‐associated protein 1</scp> mediates initial cell survival during lorlatinib treatment through <scp>AKT</scp> signaling in <scp>ROS1</scp>‐rearranged lung cancer
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- Masatoshi Yamazoe
- Department of Respiratory Medicine, Graduate School of Medicine Kyoto University Kyoto Japan
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- Hiroaki Ozasa
- Department of Respiratory Medicine, Graduate School of Medicine Kyoto University Kyoto Japan
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- Takahiro Tsuji
- Department of Respiratory Medicine, Graduate School of Medicine Kyoto University Kyoto Japan
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- Tomoko Funazo
- Department of Respiratory Medicine, Graduate School of Medicine Kyoto University Kyoto Japan
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- Hiroshi Yoshida
- Department of Respiratory Medicine, Graduate School of Medicine Kyoto University Kyoto Japan
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- Kentaro Hashimoto
- Department of Respiratory Medicine, Graduate School of Medicine Kyoto University Kyoto Japan
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- Kazutaka Hosoya
- Department of Respiratory Medicine, Graduate School of Medicine Kyoto University Kyoto Japan
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- Tatsuya Ogimoto
- Department of Respiratory Medicine, Graduate School of Medicine Kyoto University Kyoto Japan
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- Hitomi Ajimizu
- Department of Respiratory Medicine, Graduate School of Medicine Kyoto University Kyoto Japan
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- Hironori Yoshida
- Department of Respiratory Medicine, Graduate School of Medicine Kyoto University Kyoto Japan
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- Ryo Itotani
- Department of Respiratory Medicine, Graduate School of Medicine Kyoto University Kyoto Japan
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- Yuichi Sakamori
- Department of Respiratory Medicine, Graduate School of Medicine Kyoto University Kyoto Japan
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- Kiyomitsu Kuninaga
- Department of Respiratory Medicine, Graduate School of Medicine Kyoto University Kyoto Japan
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- Wataru Aoki
- Division of Applied Life Sciences, Graduate School of Agriculture Kyoto University Kyoto Japan
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- Toyohiro Hirai
- Department of Respiratory Medicine, Graduate School of Medicine Kyoto University Kyoto Japan
Description
<jats:title>Abstract</jats:title><jats:p>Tyrosine kinase inhibitors (TKIs) that target the ROS proto‐oncogene 1, receptor tyrosine kinase (<jats:italic>ROS1</jats:italic>) gene have shown dramatic therapeutic effects in patients with ROS1‐rearranged non‐small‐cell lung cancer (NSCLC). Nevertheless, advanced ROS1‐rearranged NSCLC is rarely cured as a portion of the tumor cells can survive the initial stages of ROS1‐TKI treatment, even after maximum tumor shrinkage. Therefore, understanding the mechanisms underlying initial cell survival during ROS1‐TKI treatment is necessary to prevent cell survival and achieve a cure for ROS1‐rearranged NSCLC. In this study, we clarified the initial survival mechanisms during treatment with lorlatinib, a ROS1 TKI. First, we established a patient‐derived ezrin gene‐ROS1‐rearranged NSCLC cell line (KTOR71). Then, following proteomic analysis, we focused on yes‐associated protein 1 (YAP1), which is a major mediator of the Hippo pathway, as a candidate factor involved in cell survival during early lorlatinib treatment. Yes‐associated protein 1 was activated by short‐term lorlatinib treatment both in vitro and in vivo. Genetic inhibition of <jats:italic>YAP1</jats:italic> using siRNA, or pharmacological inhibition of YAP1 function by the YAP1‐inhibitor verteporfin, enhanced the sensitivity of KTOR71 cells to lorlatinib. In addition, the prosurvival effect of YAP1 was exerted through the reactivation of AKT. Finally, combined therapy with verteporfin and lorlatinib was found to achieve significantly sustained tumor remission compared with lorlatinib monotherapy in vivo. These results suggest that YAP1 could mediate initial cell resistance to lorlatinib in KTOR71 cells. Thus, combined therapy targeting both YAP1 and ROS1 could potentially improve the outcome of ROS1‐rearranged NSCLC.</jats:p>
Journal
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- Cancer Science
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Cancer Science 114 (2), 546-560, 2022-11-23
Wiley
