Navitoclax enhances the effectiveness of EGFR-targeted antibody-drug conjugates in PDX models of EGFR-expressing triple-negative breast cancer.
Navitoclax enhances the effectiveness of EGFR-targeted antibody-drug conjugates in PDX models of EGFR-expressing triple-negative breast cancer.
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Navitoclax在表达EGFR的三阴性乳腺癌的PDX模型中增强了EGFR靶向的抗体 - 药物结合物的有效性。
DOI：
10.1186/s13058-020-01374-8
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发表时间：
2020-11-30
期刊：
影响因子：
--
通讯作者：
Brugge JS
中科院分区：
文献类型：
--
作者：
Zoeller JJ;Vagodny A;Daniels VW;Taneja K;Tan BY;DeRose YS;Fujita M;Welm AL;Letai A;Leverson JD;Blot V;Bronson RT;Dillon DA;Brugge JS
三阴性乳腺癌（TNBC）的靶向治疗是有限的;然而，表皮生长因子受体（EGFR）代表了一个潜在的目标，因为大多数TNBC表达EGFR。这些研究的目的是评价两种EGFR靶向抗体-药物缀合物（ADC：ABT-414; ABBV-321）与navitoclax（抗凋亡BCL-2和BCL-XL蛋白的拮抗剂）组合的有效性，以评估这些组合对TNBC的翻译相关性。在TNBC的多个患者来源的异种移植物（PDX）模型中评价组合治疗的临床前功效。使用基于显微镜的动态BH 3谱（DBP）评估navitoclax和/或ADC治疗诱导的线粒体凋亡信号传导，并在46例三阴性患者肿瘤中分析EGFR和BCL-2/XL的表达。用navitoclax加ABT-414治疗导致7个PDX中的5个的肿瘤生长显著减少，并且在最高EGFR表达的PDX中导致显著的肿瘤消退。Navitoclax + ABBV-321（一种EGFR靶向ADC，显示更有效的野生型EGFR靶向）在评价的两种最高EGFR表达模型中引起更显著的肿瘤生长抑制和消退。通过DBP测量的由单一或组合药物治疗诱导的线粒体凋亡信号传导水平与体内观察到的治疗反应相关。最后，发现大多数三阴性患者肿瘤表达EGFR并共表达BCL-XL和/或BCL-2。在临床前TNBC模型中使用组合药剂实现的显著肿瘤消退强调了BCL-2/XL拮抗剂增强EGFR靶向ADC的有效性的能力，并强调了使用此类靶向ADC减轻与BCL-2/XL抑制剂和全身化疗的组合相关的毒性的临床潜力。
Targeted therapies for triple-negative breast cancer (TNBC) are limited; however, the epidermal growth factor receptor (EGFR) represents a potential target, as the majority of TNBC express EGFR. The purpose of these studies was to evaluate the effectiveness of two EGFR-targeted antibody-drug conjugates (ADC: ABT-414; ABBV-321) in combination with navitoclax, an antagonist of the anti-apoptotic BCL-2 and BCL-XL proteins, in order to assess the translational relevance of these combinations for TNBC. The pre-clinical efficacy of combined treatments was evaluated in multiple patient-derived xenograft (PDX) models of TNBC. Microscopy-based dynamic BH3 profiling (DBP) was used to assess mitochondrial apoptotic signaling induced by navitoclax and/or ADC treatments, and the expression of EGFR and BCL-2/XL was analyzed in 46 triple-negative patient tumors. Treatment with navitoclax plus ABT-414 caused a significant reduction in tumor growth in five of seven PDXs and significant tumor regression in the highest EGFR-expressing PDX. Navitoclax plus ABBV-321, an EGFR-targeted ADC that displays more effective wild-type EGFR-targeting, elicited more significant tumor growth inhibition and regressions in the two highest EGFR-expressing models evaluated. The level of mitochondrial apoptotic signaling induced by single or combined drug treatments, as measured by DBP, correlated with the treatment responses observed in vivo. Lastly, the majority of triple-negative patient tumors were found to express EGFR and co-express BCL-XL and/or BCL-2. The dramatic tumor regressions achieved using combined agents in pre-clinical TNBC models underscore the abilities of BCL-2/XL antagonists to enhance the effectiveness of EGFR-targeted ADCs and highlight the clinical potential for usage of such targeted ADCs to alleviate toxicities associated with combinations of BCL-2/XL inhibitors and systemic chemotherapies.
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