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FGFR1过表达通过受体酪氨酸激酶信号介导的雌激素受体激活，促进腔面型乳腺癌细胞对PI3K抑制剂阿培利司产生耐药性。

FGFR1 overexpression promotes resistance to PI3K inhibitor alpelisib in luminal breast cancer cells through receptor tyrosine kinase signaling-mediated activation of the estrogen receptor.

作者信息

Shi Yujie, Chen Lexia, Cheng Qiong, Niu Peijia, Weng Yahan, Yang Xiaohe

机构信息

Department of Pathology, People's Hospital of Zhengzhou University, Zhengzhou 450003, Henan, China.

Department of Pathology, Fuwai Central China Cardiovascular Hospital, Zhengzhou 450003, Henan, China.

出版信息

Cancer Drug Resist. 2025 May 28;8:24. doi: 10.20517/cdr.2024.181. eCollection 2025.

DOI:10.20517/cdr.2024.181
PMID:40510030
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12159599/
Abstract

Resistance to PI3K inhibitor alpelisib is an emerging challenge in breast cancer treatment. FGFR1 is frequently amplified in breast cancer. We investigated FGFR1 overexpression-mediated alpelisib resistance and its mechanism. CCK-8, colony formation, and cell cycle assays assessed FGFR1 overexpression-induced alpelisib resistance in MCF-7 and T47D cells. FGFR1 siRNA knockdown validated FGFR1's role. Akt, Erk, and ER signaling were analyzed by Western blot. Synergistic effects of alpelisib with AZD4547 and fulvestrant were evaluated using the combination index. FGFR1 overexpression conferred alpelisib resistance in MCF-7 and T47D cells, evidenced by increased viability, colony formation, and S-phase accumulation post alpelisib treatment. Knockdown of FGFR1 reverse alpelisib resistance in FGFR1 overexpressing MCF-7 and T47D cells. Resistance correlated with sustained activation of Akt and Erk1/2 pathways (p-Akt, p-Erk1/2, p-S6K, p-Rb) and attenuated suppression of ERα phosphorylation (S118/S167), highlighting RTK-ER crosstalk. Combining alpelisib with AZD4547 synergistically inhibited growth and suppressed both RTK signaling and ERα phosphorylation. While alpelisib-fulvestrant was effective, adding AZD4547 further enhanced inhibition, supporting triple therapy to overcome resistance. Our findings establish FGFR1 as a key mediator of alpelisib resistance in ER+ breast cancer. Combining FGFR1 inhibitors with alpelisib-based therapies offers a viable approach for FGFR1-overexpressing tumors.

摘要

对PI3K抑制剂阿培利司的耐药性是乳腺癌治疗中一个新出现的挑战。FGFR1在乳腺癌中经常扩增。我们研究了FGFR1过表达介导的阿培利司耐药性及其机制。采用CCK-8、集落形成和细胞周期分析评估FGFR1过表达诱导的MCF-7和T47D细胞对阿培利司的耐药性。FGFR1 siRNA敲低验证了FGFR1的作用。通过蛋白质免疫印迹分析Akt、Erk和雌激素受体（ER）信号通路。使用联合指数评估阿培利司与AZD4547和氟维司群的协同作用。FGFR1过表达赋予MCF-7和T47D细胞对阿培利司的耐药性，表现为阿培利司处理后细胞活力增加、集落形成以及S期积累。敲低FGFR1可逆转FGFR1过表达的MCF-7和T47D细胞对阿培利司的耐药性。耐药性与Akt和Erk1/2通路（p-Akt、p-Erk1/2、p-S6K、p-Rb）的持续激活以及ERα磷酸化（S118/S167）抑制减弱相关，突出了受体酪氨酸激酶（RTK）-ER信号串扰。阿培利司与AZD4547联合使用可协同抑制生长，并抑制RTK信号传导和ERα磷酸化。虽然阿培利司-氟维司群有效，但添加AZD4547进一步增强了抑制作用，支持三联疗法以克服耐药性。我们的研究结果确定FGFR1是雌激素受体阳性（ER+）乳腺癌中阿培利司耐药的关键介质。将FGFR1抑制剂与基于阿培利司的疗法联合使用为FGFR1过表达肿瘤提供了一种可行的方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfe/12159599/94dd56fcd425/cdr-8-24.fig.10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfe/12159599/efcd1bf6a510/cdr-8-24.fig.1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfe/12159599/399aee8d9883/cdr-8-24.fig.2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfe/12159599/5b7b5e6e2f02/cdr-8-24.fig.7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfe/12159599/3e460ecb9594/cdr-8-24.fig.8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfe/12159599/7b390fc6b615/cdr-8-24.fig.9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfe/12159599/94dd56fcd425/cdr-8-24.fig.10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfe/12159599/efcd1bf6a510/cdr-8-24.fig.1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfe/12159599/399aee8d9883/cdr-8-24.fig.2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfe/12159599/6753b41d2f04/cdr-8-24.fig.3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfe/12159599/3e7ab7c5ed6c/cdr-8-24.fig.4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfe/12159599/93873341f986/cdr-8-24.fig.5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfe/12159599/cd1e5cf9fcbd/cdr-8-24.fig.6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfe/12159599/5b7b5e6e2f02/cdr-8-24.fig.7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfe/12159599/3e460ecb9594/cdr-8-24.fig.8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfe/12159599/7b390fc6b615/cdr-8-24.fig.9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfe/12159599/94dd56fcd425/cdr-8-24.fig.10.jpg

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Resistance to Targeted Inhibitors of the PI3K/AKT/mTOR Pathway in Advanced Oestrogen-Receptor-Positive Breast Cancer.晚期雌激素受体阳性乳腺癌对PI3K/AKT/mTOR通路靶向抑制剂的耐药性
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FGFR families: biological functions and therapeutic interventions in tumors.成纤维细胞生长因子受体家族：肿瘤中的生物学功能与治疗干预
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PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.PI3K/AKT/mTOR 信号转导通路与癌症的靶向治疗。
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Current progress in cancer treatment by targeting FGFR signaling.通过靶向成纤维细胞生长因子受体（FGFR）信号传导进行癌症治疗的当前进展。
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