The TROP2 targeting antibody-drug conjugate IMMU-132 enhances the efficacy of radiation therapy for lung cancer

Abstract Studies suggest that the human trophoblast cell-surface antigen (TROP2) is highly expressed in most lung cancers and is associated with poor prognosis. Currently, there are no TROP2-directed ADCs approved for treating lung cancer patients. IMMU-132 ADC (Sacituzumab govitecan) is a TROP-2-directed ADC recently approved for metastatic triple-negative breast cancer and urothelial cancer. However, its role in non-small cell carcinoma (NSCLC) has not been explored. Here, we examined the impact of IMMU-132 alone and in combination with radiation on NSCLC cells in vitro and in vivo.We found cell surface expression of TROP-2 on NSCLC cell lines, internalization of IMMU-132, induction of cell cycle arrest at the G2/M phase, and promotion of programmed cell death (apoptosis) following irradiation. Furthermore, IMMU-132 enhanced radiosensitivity by decreasing clonogenic survival through increased DNA double-strand break formation (as indicated by the γH2AX level), modulating DNA damage repair, inhibiting survival pathways, and inducing PARP-mediated apoptosis. In vivo, the combination of IMMU-132 and radiation therapy increased tumor control and improved overall survival in mice bearing H441 and H460 cell xenografts, as well as in the syngeneic LLC tumor. Tumor radio-sensitization with IMMU-132 promotes the inhibition of prosurvival signaling (PI3K/AKT/mTOR/, MEK/ERK, p38MAPK/JNK) together with induced apoptosis by increasing PARP, cleaved caspase-3 and reducing anti-apoptotic proteins (BCL-xL, BCL-2, XIAP) as well as modulating DNA damage repair (ATM, ATR, RAD51, p53, DNA-PK).Together, our data suggests that the targeted delivery of IMMU-132 radiosensitizer at sub-therapeutic doses could broaden the therapeutic window of radiation therapy in lung cancer and may decrease the possibility of side effects. Hence, the combination of IMMU-132 and radiation therapy could be a promising therapeutic strategy for NSCLC.