The Relationship between Trop-2, Chemotherapeutic Drugs, and Chemoresistance

**Background:** Drug resistance remains a major obstacle in cancer treatment, limiting therapeutic options and often leading to palliative care. While ATP-binding cassette (ABC) transporters like P-glycoprotein are well-known mediators of multidrug resistance, other transmembrane proteins also contribute. Trop-2 (trophoblast antigen 2, TACSTD2) is a cell surface glycoprotein minimally expressed in normal adult epithelial cells but overexpressed in many epithelial tumors, including lung, breast, colorectal, pancreatic, and urothelial cancers. Trop-2 is involved in cell adhesion, proliferation, invasion, and stemness, and its overexpression is associated with poor prognosis and metastasis. This review synthesizes evidence on Trop-2's role in chemoresistance and potential therapeutic strategies.

**Methods:** This is a narrative review summarizing published studies on Trop-2 structure, expression, signaling, and its relationship with chemoresistance. The authors reviewed literature on Trop-2's mechanisms of action, including its cleavage by ADAM10 and γ-secretase, activation of β-catenin and MAPK pathways, and calcium signaling via PIP2 hydrolysis. They also examined clinical and preclinical studies linking Trop-2 to resistance against drugs such as tamoxifen, oxaliplatin, cisplatin, gefitinib, and docetaxel. Evidence from cell lines, xenograft models, and clinical trials of Trop-2-targeted therapies (e.g., sacituzumab govitecan) was included.

**Key Results:** The review presents 14 lines of evidence supporting Trop-2's role in chemoresistance. Key findings include: (1) Trop-2 was highly expressed in 83% of 50 ovarian serous carcinoma specimens and chemo-resistant ovarian cancer cell lines were sensitive to an anti-Trop-2 monoclonal antibody in vitro (Varughese et al.). (2) Oxaliplatin induced Trop-2 overexpression in HCT-116 colon cancer xenografts, suggesting a paradoxical growth-promoting effect (Jordheim et al.). (3) A 74-year-old woman with therapy-resistant uterine serous carcinoma showed a 66% reduction in target lesions and response duration >10 months after treatment with IMMU-132 (sacituzumab govitecan) (Han et al.). (4) In a Phase I/II study of sacituzumab govitecan in platinum-resistant urothelial carcinoma, 50% of patients had a clinically significant response (Faltas et al.). (5) In heavily pretreated SCLC patients, 60% showed tumor shrinkage and a 34% clinical benefit rate with IMMU-132. (6) Trop-2 knockdown re-sensitized chemoresistant lung cancer cells and slowed xenograft growth in vivo. (7) Trop-2 downregulation increased cisplatin sensitivity in cervical cancer cell lines, with significantly more apoptotic cells after cisplatin treatment. (8) In prostate cancer, androgen-sensitive cell lines with high Trop-2 levels had increased ability to re-grow after docetaxel; Trop-2 downregulation abolished this. (9) In gastric cancer xenografts, Trop-2 knockdown increased cisplatin sensitivity, while overexpression conferred resistance; Trop-2 also upregulated MRP1 expression via Notch signaling. (10) Tamoxifen treatment significantly increased Trop-2 expression in breast luminal cancer cell lines. (11) Trop-2 bound IGF2R, promoting Akt signaling and gefitinib resistance in NSCLC. (12) Trop-2 expression was a predictor of tumor response to AKT inhibitors. (13) Sacituzumab govitecan combined with ABC transporter inhibitors restored SN38 toxicity in resistant breast and gastric cancer cells. (14) Chemo-resistant ovarian carcinoma cells were re-sensitized by Trop-2 inhibition with monoclonal antibody RS7-3G11. The review also notes controversial anti-tumoral effects of Trop-2 in cervical and breast cancers, suggesting tissue-specific roles.

**Clinical Implications:** Trop-2 is a promising therapeutic target for overcoming chemoresistance in epithelial cancers. The success of sacituzumab govitecan, an anti-Trop-2 antibody-drug conjugate approved for HR+/HER2- metastatic breast cancer, provides proof-of-concept that targeting Trop-2 can benefit patients who have failed multiple prior therapies. Trop-2 expression may serve as a biomarker for resistance to drugs like oxaliplatin, tamoxifen, and gefitinib, and its inhibition could re-sensitize tumors. Strategies to reduce Trop-2 expression, such as using Sp1 inhibitors like tolfenamic acid, warrant further investigation. However, the controversial anti-tumor effects of Trop-2 in some contexts highlight the need for tumor-specific studies. Overall, Trop-2 represents a valuable target for developing novel therapies to combat multidrug resistance.