Overcoming Resistance to Anti–Nectin-4 Antibody-Drug Conjugate

多西紫杉醇 医学 抗体-药物偶联物 P-糖蛋白 抗药性 癌症 体内 癌症研究 药理学 多重耐药 抗体 单克隆抗体 免疫学 内科学 生物 生物技术 微生物学
作者
Olivier Cabaud,Ludovic Berger,Emerence Crompot,José Adélaide,Pascal Finetti,Sèverine Garnier,Arnaud Guillé,Nadine Carbuccia,Anne Farina,Emilie Agavnian,Max Chaffanet,Anthony Gonçalvès,Emmanuelle Charafe‐Jauffret,Émilie Mamessier,Daniel Birnbaum,François Bertucci,Marc Lopez
出处
期刊:Molecular Cancer Therapeutics [American Association for Cancer Research]
卷期号:21 (7): 1227-1235 被引量:33
标识
DOI:10.1158/1535-7163.mct-22-0013
摘要

Abstract Antibody–drug conjugates (ADC) represent a fast-growing drug class in oncology. However, ADCs are associated with resistance, and therapies able to overcome it are of utmost importance. Recently, enfortumab vedotin-ejfv (EV) was approved in nectin-4+ metastatic urothelial cancer. We previously described PVRL4/nectin-4 as a new therapeutic target in breast cancer and produced an efficient EV-like ADC comprising a human anti–nectin-4 mAb conjugated to monomethyl auristatin-E (MMAE) named N41mab-vcMMAE. To study the consequence of the long-term treatment with this ADC, we developed a preclinical breast cancer model in mice, and report a mechanism of resistance to N41mab-vcMMAE after 9-month treatment and a way to reverse it. RNA-sequencing pointed to an upregulation in resistant tumors of ABCB1 expression, encoding the multidrug resistance protein MDR-1/P-glycoprotein (P-gp), associated with focal gene amplification and high protein expression. Sensitivity to N41mab-vcMMAE of the resistant model was restored in vitro by P-gp pharmacologic inhibitors, like tariquidar. P-gp is expressed in a variety of normal tissues. By delivering the drug to the tumor more specifically than classical chemotherapy, we hypothesized that the combined use of ADC with P-gp inhibitors might reverse resistance in vivo without toxicity. Indeed, we showed that the tariquidar/N41mab-vcMMAE combination was well tolerated and induced a rapid regression of ADC-resistant tumors in mice. In contrast, the tariquidar/docetaxel combination was toxic and poorly efficient. These results show that ABC transporter inhibitors can be safely used with ADC to reverse ADC-induced resistance and open new opportunities in the fight against multidrug resistance.
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