mTOR-mediated p62/SQSTM1 stabilization confers a robust survival mechanism for ovarian cancer

Tomohiro Tamura; Shimpei Nagai; Kenta Masuda; Keiyo Imaeda; Eiji Sugihara; Juntaro Yamasaki; Miho Kawaida; Yuji Otsuki; Kentaro Suina; Hiroyuki Nobusue; Tomoko Akahane; Tatsuyuki Chiyoda; Iori Kisu; Yusuke Kobayashi; Kouji Banno; Kazuhiro Sakurada; Hajime Okita; Rui Yamaguchi; Ahmed Ashour Ahmed; Wataru Yamagami; Hideyuki Saya; Daisuke Aoki; Osamu Nagano

doi:10.1016/j.canlet.2025.217565

mTOR-mediated p62/SQSTM1 stabilization confers a robust survival mechanism for ovarian cancer

Tomohiro Tamura, Shimpei Nagai, Kenta Masuda, Keiyo Imaeda, Eiji Sugihara, Juntaro Yamasaki, Miho Kawaida, Yuji Otsuki, Kentaro Suina, Hiroyuki Nobusue, Tomoko Akahane, Tatsuyuki Chiyoda, Iori Kisu, Yusuke Kobayashi, Kouji Banno, Kazuhiro Sakurada, Hajime Okita, Rui Yamaguchi, Ahmed Ashour Ahmed, Wataru YamagamiHideyuki Saya, Daisuke Aoki, Osamu Nagano

Research output: Contribution to journal › Article › peer-review

Abstract

Over 50 % of patients with high-grade serous carcinoma (HGSC) are homologous recombination proficient, making them refractory to platinum-based drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. These patients often develop progressive resistance within 6 months after primary treatment and tend to die early, thus new therapies are urgently needed. In this study, we comprehensively investigated this tumor type by leveraging a combination of machine learning analysis of a large published dataset and newly developed genetically engineered HGSC organoid models from murine fallopian tubes. Aberrant activation of RAS/PI3K signaling was a signature of poor prognosis in BRCA1/2 wild-type ovarian cancer, and mTOR-induced elevated p62 expression was a robust marker of chemotherapy-induced mTOR-p62-NRF2 signal activation. mTOR inhibition with everolimus decreased p62 and enhanced sensitivity to conventional chemotherapy, indicating that p62 serves as an important biomarker for therapeutic intervention. Combination therapy with conventional chemotherapy and mTOR inhibitors is a promising therapeutic strategy for refractory HGSC, with p62 as a biomarker.

Original language	English
Article number	217565
Journal	Cancer Letters
Volume	616
DOIs	https://doi.org/10.1016/j.canlet.2025.217565
Publication status	Published - 2025 Apr 28

Keywords

BRCA1/2 wild type
Ovarian cancer
mTOR inhibitor
p62/SQSTM1

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.canlet.2025.217565

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Tamura, T., Nagai, S., Masuda, K., Imaeda, K., Sugihara, E., Yamasaki, J., Kawaida, M., Otsuki, Y., Suina, K., Nobusue, H., Akahane, T., Chiyoda, T., Kisu, I., Kobayashi, Y., Banno, K., Sakurada, K., Okita, H., Yamaguchi, R., Ahmed, A. A., ... Nagano, O. (2025). mTOR-mediated p62/SQSTM1 stabilization confers a robust survival mechanism for ovarian cancer. Cancer Letters, 616, Article 217565. https://doi.org/10.1016/j.canlet.2025.217565

Tamura, T, Nagai, S, Masuda, K, Imaeda, K, Sugihara, E, Yamasaki, J, Kawaida, M, Otsuki, Y, Suina, K, Nobusue, H, Akahane, T, Chiyoda, T , Kisu, I, Kobayashi, Y, Banno, K, Sakurada, K, Okita, H, Yamaguchi, R, Ahmed, AA, Yamagami, W, Saya, H, Aoki, D & Nagano, O 2025, 'mTOR-mediated p62/SQSTM1 stabilization confers a robust survival mechanism for ovarian cancer', Cancer Letters, vol. 616, 217565. https://doi.org/10.1016/j.canlet.2025.217565

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title = "mTOR-mediated p62/SQSTM1 stabilization confers a robust survival mechanism for ovarian cancer",

abstract = "Over 50 % of patients with high-grade serous carcinoma (HGSC) are homologous recombination proficient, making them refractory to platinum-based drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. These patients often develop progressive resistance within 6 months after primary treatment and tend to die early, thus new therapies are urgently needed. In this study, we comprehensively investigated this tumor type by leveraging a combination of machine learning analysis of a large published dataset and newly developed genetically engineered HGSC organoid models from murine fallopian tubes. Aberrant activation of RAS/PI3K signaling was a signature of poor prognosis in BRCA1/2 wild-type ovarian cancer, and mTOR-induced elevated p62 expression was a robust marker of chemotherapy-induced mTOR-p62-NRF2 signal activation. mTOR inhibition with everolimus decreased p62 and enhanced sensitivity to conventional chemotherapy, indicating that p62 serves as an important biomarker for therapeutic intervention. Combination therapy with conventional chemotherapy and mTOR inhibitors is a promising therapeutic strategy for refractory HGSC, with p62 as a biomarker.",

keywords = "BRCA1/2 wild type, Ovarian cancer, mTOR inhibitor, p62/SQSTM1",

author = "Tomohiro Tamura and Shimpei Nagai and Kenta Masuda and Keiyo Imaeda and Eiji Sugihara and Juntaro Yamasaki and Miho Kawaida and Yuji Otsuki and Kentaro Suina and Hiroyuki Nobusue and Tomoko Akahane and Tatsuyuki Chiyoda and Iori Kisu and Yusuke Kobayashi and Kouji Banno and Kazuhiro Sakurada and Hajime Okita and Rui Yamaguchi and Ahmed, {Ahmed Ashour} and Wataru Yamagami and Hideyuki Saya and Daisuke Aoki and Osamu Nagano",

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day = "28",

doi = "10.1016/j.canlet.2025.217565",

language = "English",

volume = "616",

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T1 - mTOR-mediated p62/SQSTM1 stabilization confers a robust survival mechanism for ovarian cancer

AU - Tamura, Tomohiro

AU - Nagai, Shimpei

AU - Masuda, Kenta

AU - Imaeda, Keiyo

AU - Sugihara, Eiji

AU - Yamasaki, Juntaro

AU - Kawaida, Miho

AU - Otsuki, Yuji

AU - Suina, Kentaro

AU - Nobusue, Hiroyuki

AU - Akahane, Tomoko

AU - Chiyoda, Tatsuyuki

AU - Kisu, Iori

AU - Kobayashi, Yusuke

AU - Banno, Kouji

AU - Sakurada, Kazuhiro

AU - Okita, Hajime

AU - Yamaguchi, Rui

AU - Ahmed, Ahmed Ashour

AU - Yamagami, Wataru

AU - Saya, Hideyuki

AU - Aoki, Daisuke

AU - Nagano, Osamu

PY - 2025/4/28

Y1 - 2025/4/28

N2 - Over 50 % of patients with high-grade serous carcinoma (HGSC) are homologous recombination proficient, making them refractory to platinum-based drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. These patients often develop progressive resistance within 6 months after primary treatment and tend to die early, thus new therapies are urgently needed. In this study, we comprehensively investigated this tumor type by leveraging a combination of machine learning analysis of a large published dataset and newly developed genetically engineered HGSC organoid models from murine fallopian tubes. Aberrant activation of RAS/PI3K signaling was a signature of poor prognosis in BRCA1/2 wild-type ovarian cancer, and mTOR-induced elevated p62 expression was a robust marker of chemotherapy-induced mTOR-p62-NRF2 signal activation. mTOR inhibition with everolimus decreased p62 and enhanced sensitivity to conventional chemotherapy, indicating that p62 serves as an important biomarker for therapeutic intervention. Combination therapy with conventional chemotherapy and mTOR inhibitors is a promising therapeutic strategy for refractory HGSC, with p62 as a biomarker.

AB - Over 50 % of patients with high-grade serous carcinoma (HGSC) are homologous recombination proficient, making them refractory to platinum-based drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. These patients often develop progressive resistance within 6 months after primary treatment and tend to die early, thus new therapies are urgently needed. In this study, we comprehensively investigated this tumor type by leveraging a combination of machine learning analysis of a large published dataset and newly developed genetically engineered HGSC organoid models from murine fallopian tubes. Aberrant activation of RAS/PI3K signaling was a signature of poor prognosis in BRCA1/2 wild-type ovarian cancer, and mTOR-induced elevated p62 expression was a robust marker of chemotherapy-induced mTOR-p62-NRF2 signal activation. mTOR inhibition with everolimus decreased p62 and enhanced sensitivity to conventional chemotherapy, indicating that p62 serves as an important biomarker for therapeutic intervention. Combination therapy with conventional chemotherapy and mTOR inhibitors is a promising therapeutic strategy for refractory HGSC, with p62 as a biomarker.

KW - BRCA1/2 wild type

KW - Ovarian cancer

KW - mTOR inhibitor

KW - p62/SQSTM1

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SN - 0304-3835

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JO - Cancer Letters

JF - Cancer Letters

M1 - 217565

ER -

mTOR-mediated p62/SQSTM1 stabilization confers a robust survival mechanism for ovarian cancer

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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