PO.ET01.03 · 实验与分子治疗

预测性生物标志物及联合策略：克服 SCLC 中对携带拓扑异构酶 I 抑制剂载荷的 HER2 和 TROP2 靶向抗体药物偶联物的耐药

Predictive biomarkers and combination strategies to overcome resistance to HER2- and TROP2-directed antibody drug conjugates with topoisomerase I inhibitor payloads in SCLC

编号 4544 展板 12 时间 4/21 09:00–12:00 区域 Section 16 主讲 Kavya Ramkumar, PhD

分会场 Next-Generation Targeted Therapies Directed Against Tumor Surface Antigens

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作者与单位 Authors & Affiliations

Kavya Ramkumar, C. Allison Stewart, Shui-Ping So, Runsheng Wang, Azusa Tanimoto, Alberto Duarte Jr., Jenna H. Gray, Li Shen, Lixia Diao, Yuanxin Xi, Qi Wang, Alejandra G. Serrano, Luisa M. Solis Soto, Jing Wang, Bingnan Zhang, Carl M. Gay, Lauren A. Byers

UT MD Anderson Cancer Center, Houston, TX

摘要 Abstract

中文摘要

初治小细胞肺癌（SCLC）对一线化疗高度敏感；然而复发性 SCLC 获得广泛的化疗耐药，使得如拓扑替康（topotecan，一种拓扑异构酶抑制剂，TOP1i）等传统二线药物在很大程度上失效。近期采用表面靶向策略（如携带 TOP1i 类载荷的抗体药物偶联物 ADC）的临床试验已在复发性 SCLC 中显示出强烈应答。识别对这些药物应答和耐药的生物标志物对于优化这一新型治疗类别的疗效将十分重要。我们此前曾表明，非神经内分泌 SCLC 肿瘤表达低水平的 DLL3 和 SEZ6，但高水平表达 TACSTD2（TROP2）和 ERBB2（HER2）。在本研究中，我们考察了携带 TOP1i 类和非 TOP1i 类载荷的不同 HER2 和 TROP2 靶向 ADC 在 SCLC 细胞系中的活性。虽然靶点表达与 ADC 敏感性并不相关，但 SLFN11 水平高的 SCLC 细胞系对基于 TOP1i 的 HER2 和 TROP2-ADC 及其载荷表现出更高敏感性。SLFN11 敲低证实，SLFN11 缺失会降低 ADC 敏感性。值得注意的是，与 ATR 抑制剂联用可使 SLFN11 低表达的耐药 SCLC 细胞系对基于 TOP1i 的 ADC 增敏。相比之下，对一种非 TOP1i 类 HER2 ADC 的敏感性与 SLFN11 表达无关。cMYC 和 ABCB1（P-糖蛋白）高水平也与对基于 TOP1i 的 ADC 耐药相关，但与非 TOP1i ADC 无关。在机制上，基于 TOP1i 的 HER2 和 TROP2-ADC 诱导了显著的 DNA 损伤和凋亡。还检测到 PDL-1 表达升高、STING-趋化因子 CCL5 以及细胞外 ATP 的增加，提示诱导了免疫原性应答，并支持与免疫疗法的联合。总体而言，这些结果确定 SLFN11 是用于患者选择的临床生物标志物，并为联合 ATR 抑制剂或使用替代的非 TOP1i 类 ADC 以克服对基于 TOP1i 的 HER2 和 TROP2-ADC 耐药提供了临床前支持。

查看英文原文 English abstract

Treatment-naïve small cell lung cancer (SCLC) is highly sensitive to frontline chemotherapy; however relapsed SCLC acquires broad chemoresistance that renders conventional second line agents like topotecan, a topoisomerase inhibitor (TOP1i), largely ineffective. Recent clinical trials with surface targeting strategies such as antibody drug conjugates (ADCs) with TOP1i-based payloads have demonstrated strong responses in relapsed small SCLC. Identifying biomarkers of response and resistance to these agents will be important to optimize the effectiveness of this new therapeutic class. We previously showed that non-neuroendocrine SCLC tumors express low levels of DLL3 and SEZ6 , but high levels of TACSTD2 (TROP2) and ERBB2 (HER2). In this study, we examined the activities of different HER2- and TROP2-directed ADCs with TOP1i- and non-TOP1i-based payloads in SCLC cell lines. While target expression did not correlate with ADC sensitivity, SCLC cell lines with high SLFN11 levels showed greater sensitivity to TOP1i-based HER2- and TROP2-ADCs and their payloads. SLFN11 knockdown confirmed that SLFN11 loss reduces ADC sensitivity. Notably, combination with an ATR inhibitor sensitized resistant SLFN11-low SCLC cell lines to TOP1i-based ADCs. In contrast, sensitivity to a non-TOP1i-based HER2 ADC was not associated with SLFN11 expression. High cMYC and ABCB1 (P-glycoprotein) levels were also associated with resistance to TOP1i-based ADC, but not to non-TOP1i ADCs. Mechanistically, TOP1i-based HER2- and TROP2-ADCs induced significant DNA damage and apoptosis. Increases in PDL-1 expression, STING-chemokine CCL5, along with extracellular ATP were also detected, indicating induction of immunogenic responses and supporting combinations with immunotherapy. Overall, these results identify SLFN11 as a clinical biomarker for patient selection and provide preclinical support for combinations with ATR inhibitor or using alternate non-TOP1i-based ADCs to overcome resistance to TOP1i-based HER2- and TROP2-ADCs.

利益披露 Disclosure

K. Ramkumar, None.. C. Stewart, None.. S. So, None.. R. Wang, None.. A. Tanimoto, None.. A. Duarte Jr., None.. J. H. Gray, None.. L. Shen, None.. L. Diao, None.. Y. Xi, None.. Q. Wang, None.. A. G. Serrano, None.. L. M. Solis Soto, None.. J. Wang, None. B. Zhang, Abdera therapeutics Other, Advisory board. Oncohost Other, Advisory board. Ideology health Other, Travel speaking support. C. M. Gay, Abdera Other, Advisory Board/Steering Committee. Amgen Other, Advisory Board/Steering Committee. AstraZeneca Other, Advisory Board/Steering Committee. BeOne Other, Advisory Board/Steering Committee. BioNTech Other, Advisory Board/Steering Committee. Boehringer Ingelheim Other, Advisory Board/Steering Committee. Daiichi Sankyo Other, Advisory Board/Steering Committee. G1 Therapeutics Other, Advisory Board/Steering Committee. Jazz Pharmaceuticals Other, Advisory Board/Steering Committee. Merck Other, Advisory Board/Steering Committee. OncoHost Other, Advisory Board/Steering Committee. Roche/Genentech Other, Advisory Board/Steering Committee. L. A. Byers, AstraZeneca ), Other, Consulting/advisory roles. Amgen ), Other, consulting/advisory roles. Circle Pharma ). Bristol-Myers Squibb ). AbbVie Other, consulting/advisory roles. Boehringer Ingelheim Other, consulting/advisory roles. Chugai Pharmaceutical Co. Other, consulting/advisory roles. Daiichi Sankyo Other, consulting/advisory roles. Roche/Genentech Other, consulting/advisory roles. Jazz Pharmaceuticals Other, consulting/advisory roles. Novartis Other, consulting/advisory roles. Puma Biotechnology Other, consulting/advisory roles.

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