Evidence map›Paper›PMID 40931042›Full record

ArticleActa pharmacologica Sinica2026

HER3 upregulation reduces DS-8201 sensitivity in HER2-positive tumor cells by ATR/CHK1/FoxO1 signaling cascade.

Wen-Jing Li, Kai-Ge Kang, Yu-Xiang Zhang, Xin-Xin Zhao, Xi Zhu, Jiao Tang, Yong-Peng Li, Hao-Yu Fu, Qing Yao, Lei Wang and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Acta pharmacologica Sinica, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Wen-Jing LiShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Kai-Ge KangShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Yu-Xiang ZhangShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Xin-Xin ZhaoSchool of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Xi ZhuShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Jiao TangShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Yong-Peng LiShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Hao-Yu FuShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Qing YaoShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Lei WangShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. wanglei@simm.ac.cn.
Li-Guang LouShanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. lglou@simm.ac.cn.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

The anti-HER2 antibody‒drug conjugate (ADC) DS-8201 presents new hope for patients with advanced HER2-positive tumors. Its clinical application, however, is hindered by serious adverse reactions and reduced efficacy following long-term treatment. In this study, we investigated the factors influencing the sensitivity of DS-8201 and developed effective combination regimens to optimize its therapeutic efficacy. We showed that HER3 upregulation diminished the sensitivity of HER2-positive tumor cells to DS-8201. We found that DS-8201 treatment activated DNA damage repair responses in BT-474 cells, in which the ATR kinase pathway induced the expression of the HER3 transcription factor FoxO1, leading to increased HER3 levels. This process was triggered by the payload component of DS-8201, the topoisomerase I inhibitor DXd, rather than the antibody. Based on this finding, we showed that combining DS-8201 with either a HER3-targeting antibody (SIBP-03) or an ATR inhibitor (BAY1895344) resulted in significant synergistic antitumor efficacy without substantial toxicity in vitro or in vivo. Overall, this study revealed that the ATR/FoxO1/HER3 pathway plays a critical role in modulating the efficacy of DS-8201, suggesting that combining DS-8201 with ATR or HER3 inhibition represents a promising therapeutic strategy for HER2-positive cancers.

Indexed as

Antineoplastic AgentsBreast NeoplasmsErb-b2 Receptor Tyrosine KinasesImmunoconjugatesReceptor, ErbB-3AnimalsAtaxia Telangiectasia Mutated ProteinsCell Line, TumorCheckpoint Kinase 1FemaleForkhead Box Protein O1HumansMiceMice, Inbred BALB CMice, NudeSignal TransductionAntineoplastic AgentsAtaxia Telangiectasia Mutated ProteinsATR protein, humanCheckpoint Kinase 1CHEK1 protein, humanERBB2 protein, humanErb-b2 Receptor Tyrosine KinasesERBB3 protein, humanForkhead Box Protein O1FOXO1 protein, humanImmunoconjugatesReceptor, ErbB-3ATR inhibitorDNA damage responseDS-8201FoxO1HER2-positive tumorsHER3 upregulation

Identifiers

PMID40931042
PMCPMC12811379

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.