Usage Information

HDAC5 deficiency induces intrinsic resistance to KRAS inhibition by disrupting c-Myc acetylation-ubiquitination homeostasis
Taoyu Chen, Haixin Yu, Keshan Wang, Gengdu Qin, Yuhan Zhao, Xueyi Liang, Yuxuan Li, Tianhao Zou, Jiaying Liu, Jingyuan Zhao, Zhiqiang Liu, Ruozheng Wei, Bo Wang, Shanmiao Gou, Tao Yin, Heshui Wu, Xin Jin, Yingke Zhou
Taoyu Chen, Haixin Yu, Keshan Wang, Gengdu Qin, Yuhan Zhao, Xueyi Liang, Yuxuan Li, Tianhao Zou, Jiaying Liu, Jingyuan Zhao, Zhiqiang Liu, Ruozheng Wei, Bo Wang, Shanmiao Gou, Tao Yin, Heshui Wu, Xin Jin, Yingke Zhou
View: Text | PDF
Research Article Cell biology Oncology

HDAC5 deficiency induces intrinsic resistance to KRAS inhibition by disrupting c-Myc acetylation-ubiquitination homeostasis

Abstract

KRAS mutations serve as key oncogenic drivers in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC). Despite the advancement of KRAS inhibitors, such as MRTX1133, for PDAC treatment, intrinsic and acquired resistance remain major barriers to their clinical efficacy. This study underscored the role of histone deacetylase 5 (HDAC5) loss in mediating intrinsic resistance to KRASG12D inhibitors. Mechanistically, HDAC5 promoted c-Myc degradation by deacetylating K148, thereby facilitating NEDD4-mediated ubiquitination at this site. The loss of HDAC5 resulted in hyperacetylation of c-Myc at K148, impeding the ubiquitination and subsequent degradation process of c-Myc following deacetylation. Consequently, c-Myc stability and transcriptional activity were sustained even under KRAS/MEK/ERK pathway inhibition, reinforcing MAPK signaling and promoting cell survival despite KRAS suppression. Our data further demonstrated that pharmacological or genetic inhibition of c-Myc effectively reversed the resistance phenotype mediated by HDAC5 loss, suggesting a therapeutic strategy centered on KRAS-MYC dual-node blockade. Furthermore, the expression levels of HDAC5 and the acetylation status of c-Myc may serve as biomarkers for predicting the therapeutic response to MRTX1133. These findings provide insights into overcoming resistance to KRASG12D inhibitors and offer potential biomarkers and combinatorial therapeutic strategies for precision treatment of PDAC.

Authors

Taoyu Chen, Haixin Yu, Keshan Wang, Gengdu Qin, Yuhan Zhao, Xueyi Liang, Yuxuan Li, Tianhao Zou, Jiaying Liu, Jingyuan Zhao, Zhiqiang Liu, Ruozheng Wei, Bo Wang, Shanmiao Gou, Tao Yin, Heshui Wu, Xin Jin, Yingke Zhou

×

Usage data is cumulative from December 2025 through October 2026.

Usage JCI PMC
Text version 4,309 694
PDF 1,382 252
Figure 1,787 0
Supplemental data 1,002 86
Citation downloads 362 0
Totals 8,842 1,032
Total Views 9,874

Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.

Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.

Advertisement