Background: DS-1062a is a TROP2-targeting antibody-drug conjugate with Daiichi-Sankyo DXd technology. DS-1062a is expected to deliver DXd, a derivative of Exatecan, to TROP2 highly expressed tumors such as epithelial cancers with stronger anti-tumor effect and safer profile than the systemic chemotherapy. SLFN11 has been reported as a sensitivity biomarkers of DNA topoisomerase I inhibitors in several cancers. In this research, we elucidated the potency of combination of TROP2 and SLFN11 as a sensitive biomarkers of DS-1062a sensitivity using in vitro and in vivo preclinical models. Materials and Methods: Growth inhibition effect of DS-1062a and DXd were tested using 39 cell lines of various cancer types and correlation between DS-1062a efficacy and both TROP2 and SLFN11 mRNA level was elucidated. To confirm the contribution of SLFN11 expression to DS-1062a sensitivity, SLFN11 was knocked down in 5 of TROP2 and SLFN11 expressed cell lines and changes of growth inhibition effects of DS-1062a and DXd were evaluated. DS-1062a efficacy were also evaluated in 25 PDX (Patient-derived xenograft) models which express various levels of TROP2 and SLFN11 and relationship of sensitivity of each tumor to DS-1062a and TROP2 and SLFN11 mRNA levels was analyzed. Results: In vitro tumor cell growth inhibition effect of DS-1062a was observed in the most of TROP2 highly expressed cell lines. However, DS-1062a showed weak efficacy in some cell lines with high TROP2 expression, which have relatively low sensitivity to DXd. Correlation analysis between DXd efficacy and gene expression suggested cell lines with low sensitivity tend to express limited level of SLFN11. Knock down of SLFN11 weakened in vitro tumor cell growth inhibition effect of both DS-1062a and DXd in cell lines with high expression of SLFN11 level. Furthermore, in vivo study with 25 PDX models, strong drug efficacy of DS-1062a was frequently observed in both TROP2 and SLFN11 expressed tumor. Conclusion: We revealed that SLFN11 is one of the sensitivity biomarkers other than TROP2 expression levels against DS-1062a. This finding suggests combination of TROP2 and SLFN11 could be a promising biomarker to predict antitumor effect of DS-1062a.
Citation Format: Satoru Yasuda, Daisuke Okajima, Tadashi Toki, Junko Yamaguchi, Tsuyoshi Karibe, Tomomichi Fujitani, Takashi Nakada, Yutaka Noguchi, Masato Murakami. Combination of TROP2 and SLFN11 as the sensitivity biomarkers for DS-1062a, a novel TROP2-targeting antibody-drug conjugate with a novel DNA topoisomerase I inhibitor DXd [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A027. doi:10.1158/1535-7163.TARG-19-A027