1. Trastuzumab Deruxtecan (DS-8201a): The Latest Research and Advances in Breast Cancer
Konstantinos Koutsoukos, Flora Zagouri, Michalis Liontos, Angeliki Andrikopoulou, Meletios-Athanasios Dimopoulos, Eleni Zografos Clin Breast Cancer . 2021 Jun;21(3):e212-e219. doi: 10.1016/j.clbc.2020.08.006.
The development of antibody-drug conjugates composed of a cytotoxic agent and a monoclonal antibody carrier offers an important alternative to classic chemotherapy strategies. Trastuzumab deruxtecan (DS-8201a) is a next-generation antibody-drug conjugate composed of a monoclonal anti-HER2 antibody and a topoisomerase I inhibitor, an exatecan derivative (DX-8951f). DS-8201a resulted in favorable outcomes in HER2-positive heavily pretreated breast cancer patients and also had a promising efficacy in patients with HER2-negative/low-expressing disease, whose options are limited. Interestingly, a recently published phase 2 trial (NCT03248492) reported 60% overall response and 97% disease control in patients with HER2-positive disease previously treated with multiple regimens, including trastuzumab emtansine. On the basis of recent clinical trials, the US Food and Drug Administration granted accelerated approval to DS-8201a in advanced or unresectable HER2-positive breast cancer pretreated with at least two HER2-targeting treatment lines. We review all preclinical and clinical data of DS-8201a regarding breast cancer.
2. DS-8201a, a new HER2-targeting antibody-drug conjugate incorporating a novel DNA topoisomerase I inhibitor, overcomes HER2-positive gastric cancer T-DM1 resistance
Kazuto Nishio, Kazuko Sakai, Junji Tsurutani, Naoki Takegawa, Kazuhiko Nakagawa, Kimio Yonesaka, Yoshikane Nonagase, Osamu Maenishi, Takao Tamura, Yusuke Ogitani Int J Cancer . 2017 Oct 15;141(8):1682-1689. doi: 10.1002/ijc.30870.
Anti-HER2 therapies are beneficial for patients with HER2-positive breast or gastric cancer. T-DM1 is a HER2-targeting antibody-drug conjugate (ADC) comprising the antibody trastuzumab, a linker, and the tubulin inhibitor DM1. Although effective in treating advanced breast cancer, all patients eventually develop T-DM1 resistance. DS-8201a is a new ADC incorporating an anti-HER2 antibody, a newly developed, enzymatically cleavable peptide linker, and a novel, potent, exatecan-derivative topoisomerase I inhibitor (DXd). DS-8201a has a drug-to-antibody-ratio (DAR) of 8, which is higher than that of T-DM1 (3.5). Owing to these unique characteristics and unlike T-DM1, DS-8201a is effective against cancers with low-HER2 expression. In the present work, T-DM1-resistant cells (N87-TDMR), established using the HER2-positive gastric cancer line NCI-N87 and continuous T-DM1 exposure, were shown to be susceptible to DS-8201a. The ATP-binding cassette (ABC) transporters ABCC2 and ABCG2 were upregulated in N87-TDMR cells, but HER2 overexpression was retained. Furthermore, inhibition of ABCC2 and ABCG2 by MK571 restored T-DM1 sensitivity. Therefore, resistance to T-DM1 is caused by efflux of its payload DM1, due to aberrant expression of ABC transporters. In contrast to DM1, DXd payload of DS-8201a inhibited the growth of N87-TDMR cells in vitro. This suggests that either DXd may be a poor substrate of ABCC2 and ABCG2 in comparison to DM1, or the high DAR of DS-8201a relative to T-DM1 compensates for increased efflux. Notably, N87-TDMR xenograft tumor growth was prevented by DS-8201a. In conclusion, the efficacy of DS-8201a as a treatment for patients with T-DM1-resistant breast or gastric cancer merits investigation.
3. TOP1-DNA Trapping by Exatecan and Combination Therapy with ATR Inhibitor
Vishwas Paralkar, Juan C Vasquez, Yilun Sun, Sophia Gayle, Jinny Van Doorn, Woo Suk Choi, Yves Pommier, Ukhyun Jo, Ranjit S Bindra, Keli K Agama, Yasuhiro Arakawa, Ranjini K Sundaram, Xi Yang, Kelli Jones, Liton Kumar Saha, Yasuhisa Murai Mol Cancer Ther . 2022 Jul 5;21(7):1090-1102. doi: 10.1158/1535-7163.MCT-21-1000.
Exatecan and deruxtecan are antineoplastic camptothecin derivatives in development as tumor-targeted-delivery warheads in various formulations including peptides, liposomes, polyethylene glycol nanoparticles, and antibody-drug conjugates. Here, we report the molecular pharmacology of exatecan compared with the clinically approved topoisomerase I (TOP1) inhibitors and preclinical models for validating biomarkers and the combination of exatecan with ataxia telangiectasia and Rad3-related kinase (ATR) inhibitors. Modeling exatecan binding at the interface of a TOP1 cleavage complex suggests two novel molecular interactions with the flanking DNA base and the TOP1 residue N352, in addition to the three known interactions of camptothecins with the TOP1 residues R364, D533, and N722. Accordingly, exatecan showed much stronger TOP1 trapping, higher DNA damage, and apoptotic cell death than the classical TOP1 inhibitors used clinically. We demonstrate the value of SLFN11 expression and homologous recombination (HR) deficiency (HRD) as predictive biomarkers of response to exatecan. We also show that exatecan kills cancer cells synergistically with the clinical ATR inhibitor ceralasertib (AZD6738). To establish the translational potential of this combination, we tested CBX-12, a clinically developed pH-sensitive peptide-exatecan conjugate that selectively targets cancer cells and is currently in clinical trials. The combination of CBX-12 with ceralasertib significantly suppressed tumor growth in mouse xenografts. Collectively, our results demonstrate the potency of exatecan as a TOP1 inhibitor and its clinical potential in combination with ATR inhibitors, using SLFN11 and HRD as predictive biomarkers.
