Deciphering the mechanisms of resistance to anti-TROP2 cancer therapy using novel humanized mouse models

SUMMARY Anti-TROP2 antibody-drug conjugates are a new class of cancer drugs that have shown marked efficacy in treating aggressive cancers. One of these drugs, sacituzumab govitecan (SG), has been approved for treating advanced triple-negative breast cancer and hormone receptor-positive breast cancer. However, drug resistance significantly limits the rate of response to SG and the duration of the response. Identifying the resistance mechanism and developing counteracting strategies will have a significant impact on improving patient survival. However, the preclinical study of anti-TROP2 resistance mechanisms is impeded by the fact that all current human anti-TROP2 drugs do not recognize mouse TROP2 protein, and no spontaneous tumor models in immunocompetent hosts is available for anti-TROP2 studies. To overcome these barriers, we have generated a novel humanized TROP2 mouse model and generated spontaneous triple-negative breast cancer (TNBC) tumors in this model. We discovered that these tumors have heterogenous responses to anti-TROP2 ADC (SG). While some tumors showed remarkable responses to the treatment, others were completely refractory. We have established a unique collection of tumors and organoid lines that are either responsive or refractory to SG. These tumor models allow us for the first time to investigate the action of anti-TROP2 drugs in spontaneous tumors in immunocompetent preclinical models. Using these unique reagents, we will investigate the involvement of both cell-intrinsic and extrinsic mechanisms in anti-TROP2 drug resistance. These insights will open new avenues for future in-depth mechanistic investigations and developing strategies for improving response to anti-TROP2 cancer treatment. Project Number: 1R21CA307887-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Wenjun Guo | Institution: ALBERT EINSTEIN COLLEGE OF MEDICINE, BRONX, NY | Award Amount: $431,970 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CDPT-Y (56)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11282319