Abstract LB_A22: Advancing personalized therapies for small cell lung cancer: Exploring HER2-targeting antibody-drug conjugates (ADCs) and SLFN11 biomarker insights
Authors: Ibrahim Ali H. , Zhang Bingnan , Stewart C. Allison , Serrano Alejandra , Solis Luisa M. , Wang Wei-Lien , Ramkumar Kavya , Cardnell Robert J. , Wang Runsheng , Duarte Alberto , Diao Lixia , Xi Yuanxin , Wang Jing , Byers Lauren A. , Gay Carl M. 
Published: December 2023

Abstract
Background: Small-cell lung cancer (SCLC) is a highly aggressive malignancy constituting 15% of all lung cancers, with a 5-year survival rate of less than 7%. Our group has established four transcriptionally defined subtypes of SCLC, each with distinct cell surface targets (Gay et al, Cancer Cell 2021). Further, we identified SLFN11 (a putative DNA/RNA helicase) as a candidate biomarker of sensitivity to DNA-damaging agents, including topoisomerase I inhibitors. Despite these advances, SCLC is still treated clinically with a “one-size-fits-all” approach. Human epidermal growth factor receptor 2 (HER2/ERBB2) has been previously described in a subset of SCLCs and has been linked to poor prognosis. Notably, HER2-targeting antibody-drug conjugates (ADCs) like Trastuzumab Deruxtecan (T-DXd) (where the payload is a topoisomerase I inhibitor) have received FDA approval for various solid tumors, highlighting their therapeutic potential.
Methods: We analyzed ERBB2 mRNA expression in publicly available patient datasets and profiled HER2 protein expression in cell lines and patient-derived xenograft models by flow cytometry and IHC. We then assessed the cytotoxicity of Trastuzumab Deruxtecan in a panel of cell lines representative of the heterogeneity of SCLC to test whether levels of HER2 and/or SLFN11 predicted response.
Results: Analyses of HER2/ERBB2 in SCLC cell lines and patient-derived xenograft (PDX) models revealed an enrichment in the SCLC-POU2F3 (SCLC-P) subtype. HER2 expression was validated by IHC and flow cytometry in a subset of SCLC cell lines and PDX models. ERBB2 mRNA expression data was analyzed using publicly available SCLC patient datasets, where we uncovered high expression of ERBB2 in a subset of patient tumors. Consistent with this, single-cell RNA-Seq data revealed ERBB2 expression in POU2F3+ cells in tumors from patients with relapsed SCLC. As predicted, we found a strong correlation between the in vitro cytotoxicity of Trastuzumab Deruxtecan and both the level of surface HER2 expression and SLFN11 level. Importantly, the SCLC cell lines with the highest HER2 surface expression exhibited the lowest IC50 of Trastuzumab Deruxtecan, and the response was predicted by the presence of SLFN11.
Conclusion: We demonstrate HER2/ERBB2 mRNA and protein expression in a subset of SCLC, with enrichment in the SCLC-P subtype. Further, the FDA-approved HER2-targeting ADC Trastuzumab Deruxtecan had significant cytotoxicity, correlating with expression of the surface target (HER2) as well as with SLFN11 (a candidate predictive biomarker for the topoisomerase inhibitor payload). These findings suggest the potential of tailoring HER2-targeting strategies based on HER2 and SLFN11 expression in SCLC as an effective and personalized approach for tackling SCLC.
Citation Format: Ali H. Ibrahim, Bingnan Zhang, C. Allison Stewart, Alejandra Serrano, Luisa M. Solis, Wei-Lien Wang, Kavya Ramkumar, Robert J. Cardnell, Runsheng Wang, Alberto Duarte Jr, Lixia Diao, Yuanxin Xi, Jing Wang, Lauren A. Byers, Carl M. Gay. Advancing personalized therapies for small cell lung cancer: Exploring HER2-targeting antibody-drug conjugates (ADCs) and SLFN11 biomarker insights [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A22.