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在HER2阳性乳腺癌中，与TSC2非同义变体c.4349 C > G（p.Pro1450Arg）相关的抗HER2治疗耐药性可被CDK4/6抑制剂逆转。

Resistance to anti-HER2 therapy associated with the TSC2 nonsynonymous variant c.4349 C > G (p.Pro1450Arg) is reversed by CDK4/6 inhibitor in HER2-positive breast cancer.

作者信息

Yang Ziyan, Feng Jianguo, Jing Ji, Huang Yuan, Ye Wei-Wu, Lei Lei, Wang Xiao-Jia, Cao Wen-Ming

机构信息

Department of Breast Medical Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, 310022, China.

Cancer Center, Department of Medical Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China.

出版信息

NPJ Breast Cancer. 2023 May 9;9(1):36. doi: 10.1038/s41523-023-00542-1.

DOI:10.1038/s41523-023-00542-1
PMID:37160904
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10170158/
Abstract

HER2-positive breast cancer patients carrying the germline TSC2 nonsynonymous variant c.4349 C > G (p.Pro1450Arg) are resistant to anti-HER2 therapy. Multi-predictor in silico analysis reveals that this variant is deleterious. We explore the potential mechanism of this TSC2 variant and investigate methods for overcoming anti-HER2 resistance. TSC2 c.4349 C > G reverses the inhibitory effect on mTOR and downstream signaling by increasing TSC2 phosphorylation at Thr1462 and confers significant lapatinib resistance in vitro and in vivo. The combination of lapatinib and the CDK4/6 inhibitor palbociclib inhibits cyclin D1/CDK4/Rb alternative pathway and TSC2 phosphorylation, thereby partially attenuating mTOR activity and inducing TSC2-mutant cell blockage at G1/G0. In in vitro and xenograft models, palbociclib+lapatinib shows higher anti-tumor activity than monotherapy and overcomes the resistance of the TSC2 c.4349 C > G-related variant to anti-HER2 therapy. We reveal a new mechanism of resistance to anti-HER2 therapy and provide a strategy to increase the efficiency of anti-HER2 therapy in HER2-positive breast cancer.

摘要

携带种系TSC2非同义变体c.4349 C > G（p.Pro1450Arg）的HER2阳性乳腺癌患者对抗HER2治疗耐药。多预测因子计算机模拟分析表明该变体具有有害性。我们探究了这种TSC2变体的潜在机制，并研究克服抗HER2耐药性的方法。TSC2 c.4349 C > G通过增加Thr1462位点的TSC2磷酸化来逆转对mTOR及下游信号传导的抑制作用，并在体外和体内赋予显著的拉帕替尼耐药性。拉帕替尼与CDK4/6抑制剂哌柏西利联合使用可抑制细胞周期蛋白D1/CDK4/Rb替代途径以及TSC2磷酸化，从而部分减弱mTOR活性并诱导TSC2突变细胞在G1/G0期阻滞。在体外和异种移植模型中，哌柏西利+拉帕替尼显示出比单一疗法更高的抗肿瘤活性，并克服了TSC2 c.4349 C > G相关变体对抗HER2治疗的耐药性。我们揭示了抗HER2治疗耐药的新机制，并提供了一种提高HER2阳性乳腺癌抗HER2治疗疗效的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cf2/10170158/8a84b818dce1/41523_2023_542_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cf2/10170158/e60a01eab017/41523_2023_542_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cf2/10170158/8514f6346a7e/41523_2023_542_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cf2/10170158/3001ac03fed8/41523_2023_542_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cf2/10170158/be856919c1d7/41523_2023_542_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cf2/10170158/8a84b818dce1/41523_2023_542_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cf2/10170158/e60a01eab017/41523_2023_542_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cf2/10170158/8514f6346a7e/41523_2023_542_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cf2/10170158/3001ac03fed8/41523_2023_542_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cf2/10170158/be856919c1d7/41523_2023_542_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2cf2/10170158/8a84b818dce1/41523_2023_542_Fig5_HTML.jpg

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