Evidence map›Paper›PMID 41697749›Full record

ArticleThe Journal of clinical investigation2026

Cotargeting DNA topoisomerase II enhances efficacy of RAS-targeted therapy in KRAS-mutant cancer models.

Rongzhong Xu, Dongsheng Wang, Guangzhi Ma, Xun Yuan, Qian Chu, Songqing Fan, Rener Zhang, Pan Du, Shidong Jia, Ticiana A Leal and 3 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of clinical investigation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing 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

1 citing paper in PubMed.

  1. Article
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

13 authors.

Rongzhong XuClinical Medical Center of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Dongsheng WangDepartment of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.
Guangzhi MaDepartment of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.
Xun YuanDepartment of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Qian ChuDepartment of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Songqing FanDepartment of Pathology, The Second Xiangya Hospital, Central South University, Changsha, China.
Rener ZhangPredicine, Inc., Hayward, California, USA.
Pan DuPredicine, Inc., Hayward, California, USA.
Shidong JiaPredicine, Inc., Hayward, California, USA.
Ticiana A LealDepartment of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.
Suresh S RamalingamDepartment of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.
Zhen ChenDepartment of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.
Shi-Yong SunDepartment of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

The approval of sotorasib and adagrasib as the first KRAS G12C inhibitors has made the RAS oncogene a druggable target. However, they have modest objective response rates and short response durations. Therefore, strategies for improving RAS-targeted cancer therapy are urgently needed. Here, we found that both sotorasib and adagrasib promoted topoisomerase IIα (Topo IIα) proteasomal degradation in KRAS G12C-mutant cancer cells and induced DNA damage and apoptosis. In cell lines with acquired resistance to sotorasib, elevated Topo IIα levels were detected. TOP2A overexpression in sensitive KRAS G12C-mutant cells conferred resistance to sotorasib, whereas TOP2A knockdown in sotorasib-resistant cell lines sensitized the cells to sotorasib. Moreover, the combination of a KRAS G12C inhibitor such as sotorasib with a Topo II inhibitor such as VP-16 synergistically decreased the survival of sotorasib-resistant RAS G12C-mutant cells with augmented induction of DNA damage and apoptosis, effectively inhibited the growth of sotorasib-resistant tumors, and delayed or prevented the emergence of acquired resistance to sotorasib in vivo. Collectively, our results reveal an essential role of Topo IIα inhibition in mediating the therapeutic efficacy of RAS-targeted cancer therapy, providing a strong scientific rationale for targeting Topo II to improve RAS-targeted cancer therapies.

Indexed as

DNA Topoisomerases, Type IIMutationProto-Oncogene Proteins p21(ras)SulfonamidesTopoisomerase II InhibitorsAnimalsAntigens, NeoplasmApoptosisCell Line, TumorDNA DamageDrug Resistance, NeoplasmEtoposideHumansMicePiperazinesPoly-ADP-Ribose Binding ProteinsAntigens, NeoplasmDNA Topoisomerases, Type IIEtoposideKRAS protein, humanPiperazinesPoly-ADP-Ribose Binding ProteinsProto-Oncogene Proteins p21(ras)PyridinesPyrimidinessotorasibSulfonamidesTOP2A protein, humanTopoisomerase II InhibitorsApoptosisCell biologyDrug therapyLung cancerOncology

Identifiers

PMID41697749
PMCPMC12904700

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Registered trials

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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.