HMGCR loss is synthetic lethal with PIK3CD inhibition in colorectal cancer cells

doi:10.4251/wjgo.v18.i4.114220

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Apr 15, 2026 (publication date) through Apr 11, 2026

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World Journal of Gastrointestinal Oncology

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastrointest Oncol. Apr 15, 2026; 18(4): 114220
Published online Apr 15, 2026. doi: 10.4251/wjgo.v18.i4.114220

HMGCR loss is synthetic lethal with PIK3CD inhibition in colorectal cancer cells

Jin-Hui Huang, Jin-Qi Ma

Jin-Hui Huang, Department of Pediatrics, The Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China

Jin-Qi Ma, Department of Blood Transfusion, The Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China

Author contributions: Huang JH was responsible for methodology, formal analysis, data curation, software, investigation, writing—original draft, visualization; Ma JQ was responsible for acquisition, project administration, conceptualization, resources, supervision, writing—review & editing; both authors contributed to study conception and design, and have read and approved the final manuscript.

Institutional review board statement: The study was reviewed and approved by the IRB of the Third Xiangya Hospital of Central South University (Approval No. 2018-S124).

Institutional animal care and use committee statement: The laboratory animals were approved by the Medical Laboratory Animal Ethics Committee of the Third Xiangya Hospital of Central South University (Approval No. XMSB-2024-0037).

Conflict-of-interest statement: The authors declare no conflicts of interest in this study.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Data sharing statement: The data that support the findings of our study are available from the corresponding author Jin-Qi Ma (601237@csu.edu.cn).

Corresponding author: Jin-Qi Ma, MD, Professor, Department of Blood Transfusion, The Third Xiangya Hospital of Central South University, No. 138 Tongzipo Road, Changsha 410013, Hunan Province, China. 601237@csu.edu.cn

Received: September 16, 2025
Revised: November 23, 2025
Accepted: January 26, 2026
Published online: April 15, 2026
Processing time: 206 Days and 16.2 Hours

Abstract

BACKGROUND

Colorectal cancer (CRC) remains a prevalent malignancy with a high incidence globally. Conventional chemotherapy is limited by substantial toxicity, and the development of novel drugs faces considerable challenges. In this context, drug repurposing has emerged as a promising strategy for CRC treatment.

AIM

To explore the therapeutic potential of drug repurposing by evaluating the combined effect of atorvastatin and gefitinib in CRC.

METHODS

Integrated analysis of data from the SOLAD, CSSL, and SynLethDB databases was performed to identify synthetic lethal interactions involving PIK3CD, leading to the identification of HMGCR as a PIK3CD-interacting synthetic lethal partner. The anti-proliferative effects of atorvastatin (an HMGCR inhibitor) and gefitinib (an epidermal growth factor receptor-PIK3CD pathway inhibitor) were evaluated alone or in combination in SW480 and HCT116 CRC cells using the Cell Counting Kit-8 assay. Cell invasiveness was assessed by Transwell assay, and the expression of proteins related to the autophagy signaling pathway was measured via Western blot. An in vivo xenograft model was used to validate the combined antitumor effect.

RESULTS

Database screening revealed a synthetic lethal relationship between HMGCR and PIK3CD. Experimentally, the combination of atorvastatin and gefitinib exerted a synergistic inhibitory effect on the proliferation and invasion of CRC cells. Mechanistically, this synthetic lethality effect was mediated through the AMPK-SREBP-1 signaling pathway. In vivo, the combined treatment significantly suppressed tumor growth in a mouse xenograft model.

CONCLUSION

The combination of atorvastatin and gefitinib induces synthetic lethality in CRC via the AMPK-SREBP1 pathway, effectively inhibiting tumor proliferation and metastasis. This drug repurposing strategy presents a novel and translatable approach for CRC therapy.

Keywords: Colorectal cancer; Synthetic lethal; Atorvastatin; Gefitinib; Autophagy

Core Tip: Integrated analysis of data from the SOLAD, CSSL, and SynLethDB databases was performed to identify HMGCR as a PIK3CD-interacting synthetic lethal partner. Atorvastatin in combination with gefitinib synergistically inhibited the proliferation and metastasis of colorectal cancer (CRC) cells through a synthetic lethal effect via the AMP-activated protein kinase-sterol regulatory element-binding protein 1 signaling pathway. This study provides new research ideas for CRC treatment.