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Yes-associated protein 1 mediates initial cell survival during lorlatinib treatment through AKT signaling in ROS1-rearranged lung cancer

Yamazoe, Masatoshi 京都大学 DOI:10.14989/doctor.k24788

2023.05.23

概要

Tyrosine kinase inhibitors (TKIs) that target the ROS proto-­oncogene 1, receptor tyrosine kinase (ROS1) 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 YAP1 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. ...

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参考文献

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AU T H O R C O N T R I B U T I O N S

Conception and design: M. Yamazoe, H. Ozasa, T. Tsuji. Development

of methodology: M. Yamazoe, H. Ozasa, T. Tsuji, W. Aoki. Acquisition

of data: M. Yamazoe, H. Ozasa, W. Aoki. Analysis and interpretation

of data: M. Yamazoe, H. Ozasa, W. Aoki. Writing, review, and/or revision of the manuscript: M. Yamazoe, H. Ozasa, T. Tsuji, T. Funazo, H.

Yoshida, K. Hashimoto, K. Hosoya, T. Ogimoto, H. Ajimizu, H. Yoshida,

R. Itotani, Y. Sakamori, K. Kuninaga, W. Aoki, T. Hirai. Administrative,

technical, or material support: M. Yamazoe, H. Ozasa, T. Tsuji, T.

Funazo. Study supervision: H. Ozasa, Y. Sakamori, T. Hirai.

AC K N OW L E D G M E N T

The authors acknowledge the Center for Anatomical, Pathological,

and Forensic Medical Research, Graduate School of Medicine, Kyoto

University.

F U N D I N G I N FO R M AT I O N

This study was supported by a Research Fellowship for Young

Scientists of the Japan Society for the Promotion of Science (JSPS)

Grant Number 21 J12463 (M.Y.) and JSPS KAKENHI Grant Number

19 K08601 (H.O.).

C O N FL I C T O F I N T E R E S T

The authors have no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T

The data generated in this study are available upon request from the

corresponding author.

E T H I C A L A P P R OVA L

The study protocol was approved by the Kyoto University Graduate

School and Faculty of Medicine Ethics Committee (certification nos.

R0996, R2163).

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S U P P O R T I N G I N FO R M AT I O N

Additional supporting information can be found online in the

Supporting Information section at the end of this article.

How to cite this article: Yamazoe M, Ozasa H, Tsuji T, et al.

Yes-­associated protein 1 mediates initial cell survival during

lorlatinib treatment through AKT signaling in ROS1-­

rearranged lung cancer. Cancer Sci. 2022;00:1-15.

doi:10.1111/cas.15622

13497006, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/cas.15622 by Cochrane Japan, Wiley Online Library on [23/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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