Synergistic effects of sacituzumab govitecan and radiotherapy in preclinical models of colorectal cancer.

BACKGROUND

Although radiotherapy (RT) remains the standard of care for locally advanced colorectal cancer (CRC), intrinsic and acquired resistance frequently compromise long-term outcomes. Sacituzumab govitecan (SG)-a TROP2-directed antibody-drug conjugate-offers a targeted platform for intracellular SN-38 delivery. The aim of the present preclinical study was to investigate whether SG enhances radiosensitivity in CRC, thereby providing a preclinical rationale for the clinical evaluation of SG-based combination strategies.

METHODS

We evaluated SG-RT synergy across CRC cell lines with differential TROP2 expression (SW480, DLD-1 vs SW620, HCT116). In mechanistic studies, clonogenic assays, flow cytometry, cell counting kit-8, Western blot, and comet assays were utilized to assess cell survival, apoptosis, and DNA damage. TROP2 was knocked down or overexpressed to validate its role in radiosensitization. In vivo efficacy was evaluated by using cell-line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. Immunohistochemistry for cleaved caspase-3 (CASP3), phosphorylated histone H2AX (γ-H2AX), and Ki-67 were used to assess treatment-induced biological effects.

RESULTS

In TROP2-high CRC cell lines (SW480, DLD-1), combined SG and RT markedly inhibited proliferation, increased apoptosis, and amplified DNA double-strand breaks, as evidenced by elevated γ-H2AX expression and comet assay tail moments. Knockdown of TROP2 abrogated this synergy, whereas TROP2 overexpression restored it. In CDX and PDX models, SG combined with RT significantly suppressed tumor growth, increased cleaved CASP3 and γ-H2AX expression, and reduced Ki-67 without exacerbating systemic weight loss.

CONCLUSION

Our findings identify SG as a potent radiosensitizer, providing a strong rationale for integrating SG into neoadjuvant RT regimens for locally advanced CRC.