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GSTM2 is a key molecular determinant of resistance to SG-ARIs

Abstract

Prostate cancer (PCa) continues to threaten men’s health, and treatment targeting the androgen receptor (AR) pathway is the major therapy for PCa patients. Several second-generation androgen receptor inhibitors (SG-ARIs), including enzalutamide (ENZ), apalutamide (APA) and darolutamide (DARO), have been developed to better block the activity of AR. Unavoidably, emergence of resistance to these novel drugs still persists. Herein, we identified glutathione S-transferase Mu 2 (GSTM2) as an important determinant in the acquisition of resistance to SG-ARIs. Elevated GSTM2 was detected in enzalutamide-resistant (ENZ-R) PCa, and overexpression of GSTM2 in naïve enzalutamide-sensitive (ENZ-S) cells effectively transformed them to ENZ-R PCa. Aryl hydrocarbon receptor (AhR), the upstream transcription factor, was implicated in the overexpression of GSTM2 in ENZ-R cells. Mechanistically, GSTM2 antagonized the effect of ENZ by rescuing cells from oxidative stress-associated damage and activation of p38 MAPK pathway. Surprisingly, high GSTM2 levels also associated with cross-resistance to APA and DARO. Taking together, these results provide new insight to ameliorate resistance to SG-ARIs and improve treatment outcome.

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Fig. 1: Integrative analysis of RNA-seq and ATAC-seq indicates critical role of GSTM2 in ENZ-R PCa.
Fig. 2: Targeting GSTM2 overcomes resistance to ENZ.
Fig. 3: AhR is associated with ENZ-R phenotype caused by GSTM2.
Fig. 4: ENZ-R cells rely on endogenous remedy to survive OS-associated damage incurred by treatment.
Fig. 5: GSTM2 rescues cell fate by inhibiting the p38 MAPK pathway.
Fig. 6: GSTM2 and cross-resistance to SG-ARIs.
Fig. 7: In vivo 22Rv1 xenograft experiment.
Fig. 8: Clinical evidence of GSTM2 and the salvage system of OS damage in the acquisition of resistance to SG-ARIs.

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Acknowledgements

The research is generously supported by NIH R01 CA157429 (XL), R01 CA196634 (XL), R01 CA264652 (XL), R01 CA256893 (XL). This research is also supported by the Biospecimen Procurement & Translational Pathology, Biostatistics and Bioinformatics, Redox Metabolism, and Flow Cytometry and Immune Monitoring Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558). We thanks Dr. Alumkal Joshi for the generous sharing of the RNA-seq raw data, and Eleanor Erikson for the critical reading and editing of the manuscript.

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XL: conceptualization; CL and XL: project administration; CL and XL: investigation; CL: validation and visualization; CL, JPL, DH, YZ, NAL, MK and XL: methodology; CL, JPL, DH, YZ and NAL: data curation; CL, JPL, DH, YZ and NAL: formal analysis; XR, JL, ZZ, YQZ, LL, CW and XL: supervision; FM, XR, EF, CMN, YK, LL, CW and XL: resources; JPL, DH, YZ, NAL and XL: software; XL: funding acquisition; CL, JPL and DH: writing—original draft; XL: writing—review and editing.

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Correspondence to Xiaoqi Liu.

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Li, C., Liu, J., He, D. et al. GSTM2 is a key molecular determinant of resistance to SG-ARIs. Oncogene 41, 4498–4511 (2022). https://doi.org/10.1038/s41388-022-02444-1

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