Evidence map›Paper›PMID 42230588›Full record

ArticleNature communications2026

Mevalonate pathway rewiring driven by enhancer remodelling confers resistance to KRAS inhibitors in colorectal cancer.

Yaoyu Guo, Yi Zhong, Peishan Hu, Yufeng Chen, Wenjun Guo, Jianfeng Chen, Peiyong Guan, Zhengran Zhou, Fang Zhu, Xian Zeng and 16 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 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. Review
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

26 authors.

Yaoyu Guo *Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
Yi Zhong *Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
Peishan Hu *Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Yufeng Chen *Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
Wenjun GuoDepartment of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
Jianfeng ChenDepartment of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
Peiyong GuanCancer and Stem Cell Biology Program, Duke-National University of Singapore Medical School, Singapore, Singapore.ORCID http://orcid.org/0000-0001-9958-0137
Zhengran ZhouDepartment of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
Fang ZhuDepartment of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
Xian ZengDepartment of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
Jiuping GaoDepartment of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
Qiqing XiongThe Joint Research Center of Guangzhou University and Keele University for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou, Guangdong, P.R. China.
Zhaoliang YuDepartment of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.ORCID http://orcid.org/0009-0006-6900-2217
Chuling HuDepartment of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
Zerong CaiDepartment of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
Xiaoyu XieDepartment of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.ORCID http://orcid.org/0000-0002-1852-8546
Jing Han HongCancer and Stem Cell Biology Program, Duke-National University of Singapore Medical School, Singapore, Singapore.ORCID http://orcid.org/0000-0002-2173-9192
Jason Yongsheng ChanLaboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.ORCID http://orcid.org/0000-0002-4801-3703
Wenyu WangGuangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.ORCID http://orcid.org/0000-0001-8947-4867
Dechang DiaoDepartment of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.
Xiaojun XiaDepartment of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China.ORCID http://orcid.org/0000-0003-4444-7472
Qiang YuGenome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, Republic of Singapore.
Choon Kiat OngCancer and Stem Cell Biology Program, Duke-National University of Singapore Medical School, Singapore, Singapore.ORCID http://orcid.org/0000-0001-6402-4288
Yijun GaoDepartment of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China. gaoyj@sysucc.org.cn.
Xiaojian WuDepartment of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China. wuxjian@mail.sysu.edu.cn.ORCID http://orcid.org/0000-0002-4018-6335
Jing TanDepartment of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, China. tanjing@sysucc.org.cn.ORCID http://orcid.org/0000-0002-4605-4624

Funding

Guangzhou Science and Technology Program key projects 2023B01J1004National Natural Science Foundation of China (National Science Foundation of China) 82170188National Natural Science Foundation of China (National Science Foundation of China) 82320108015National Natural Science Foundation of China (National Science Foundation of China) 82470143
6 · The paper itself

Abstract

KRAS inhibitors (KRASi) have emerged as promising new cancer therapeutics for KRAS-mutant cancers; however, resistance remains a potential clinical challenge. Here, we show that reactivation of ERK is a hallmark of KRASi-resistant colorectal cancers (CRCs) and further demonstrate that enhancer remodeling rewires cholesterol biosynthesis through the mevalonate (MVA) pathway to confer this resistance. Mechanistically, enhancer remodeling activates MVA pathway, which facilitates the trafficking of KRAS to the membrane and sustains the MAPK signaling despite KRAS inhibition. Pharmacological inhibition of the MVA pathway with statins effectively blocks KRAS localization to the cell membrane, overcoming KRASi resistance in CRC. Together, these findings identify epigenetic-metabolic coupling of cholesterol biosynthesis as a mechanism of KRASi resistance and highlight targetable metabolic vulnerability in KRAS-mutant CRC.

Indexed as

Colorectal NeoplasmsDrug Resistance, NeoplasmMevalonic AcidProto-Oncogene Proteins p21(ras)AnimalsCell Line, TumorCholesterolEnhancer Elements, GeneticHumansHydroxymethylglutaryl-CoA Reductase InhibitorsMAP Kinase Signaling SystemMiceMutationCholesterolHydroxymethylglutaryl-CoA Reductase InhibitorsKRAS protein, humanMevalonic AcidProto-Oncogene Proteins p21(ras)

Identifiers

PMID42230588
PMCPMC13392262

What Socratic holds

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LicenceCC BY-NC-ND
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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 Socratic graph.