Sep 28

PQA 03 - Digital Health Innovation and Informatics, Patient Safety & Quality, and Radiation and Cancer Biology

2621 - Drug Repurposing: D-Drug Targets the GPC3/FGF2 Axis to Overcome Radiotherapy Resistance and Remodel Anti-Tumor Immunity In Colorectal Cancer

10:45am - 12:00pm ET

Poster Hall - Exhibit Hall A

Screen: 2

Presenter(s)

Xiaozheng Sun, - Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong

X. Sun¹, R. Xiao², M. Wu¹, D. Chen³, and J. Yu³; ¹Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China, ²Shandong Cancer Hospital and Institute, Jinan, shandong, China, ³Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China

Purpose/Objective(s):

Microsatellite stable (MSS) colorectal cancer (CRC) comprises over 85% of all CRC cases. Although RT combined with immunotherapy outcomes for the most solid tumor patients, MSS CRC patients failed to benefit from this combination treatment due to immune escape following radiotherapy. Proteoglycans are widely distributed in the tumor microenvironment (TME) and promote tumor progression, but their role in RT resistance remains unclear. Here, we aim to investigate the role of proteoglycans in RT-related immune escape and employ a drug repurposing approach to screen FDA-approved drugs targeting proteoglycans to sensitize RT and trigger anti-tumor immunity.

Materials/Methods:

Analyze TCGA database and perform multiplex immunohistochemistry (mIHC) on MSS CRC tissues to explore the correlation between proteoglycans and prognosis and identify candidate target genes. Virtual molecular docking combined with surface plasmon resonance (SPR) was utilized to screen and identify the FDA-approved drugs that binding to the candidate gene. Confirm the effect of candidate genes or drugs on radiotherapy resistance in vitro and in vivo. RNA-sequencing and proteomics analyses were conducted to elucidate the mechanisms. Finally, evaluate the anti-tumor efficacy of a triple-combination of candidate drug, RT and anti-PD-1 in MSS CRC models.

Results:

TCGA analysis indicated that the GPC proteoglycan family correlates negatively with RT prognosis. mIHC analysis confirmed that high GPC3 expression in MSS CRC tissues was significantly associated with poor RT outcomes. Then, we demonstrated that GPC3 suppresses CRC cells’ sensitivity to RT and impairs CD8⁺ T cell infiltration and effector functions within the TME. Subsequently, D-drug was screened as a potential GPC3 inhibitor, and its combination with RT significantly promotes apoptosis of CRC cell lines and MSS PDOs. This synergistic effect was validated in vivo. We also observed that D-drug enhanced the infiltration and effector functions of CD8⁺ T cells, whilst the triple combination of D-drug, RT, and anti-PD-1 further suppressed MSS CRC growth. Mechanistically, D-drug competitively binds GPC3 to inhibit the downstream FGF2 signalling pathway, thereby inhibiting radiotherapy-induced DNA damage repair. This promotes immunogenic cell death in tumor cells, subsequently enhancing the antitumor response of CD8⁺ T cells.

Conclusion:

This study provides the first evidence that GPC3 proteoglycan is a key regulator of RT resistance in MSS CRC. Through a drug repurposing strategy, we discovered that D-drug alleviates RT resistance in MSS CRC by targeting GPC3. This approach exhibited high efficacy with low toxicity, offering substantial translational potential. It provides a robust theoretical and experimental foundation for advancing neoadjuvant treatment paradigms for MSS CRC.