Targeting EphA2 and DDR signaling can overcome the BRAF and MEK inhibitors acquired resistance in melanoma cell lines

Translational Medicine Communications

Research

Giuseppe Argenziano¹  Mimmo Turano²  Maria Furia²  Fortunato Ciardiello³  Valentina Belli³  Erika Martinelli³  Stefania Napolitano³  Floriana Morgillo³  Teresa Troiani³  Carminia Maria Della Corte³  Giulia Martini³  Gabriella Suarato³  Vincenzo De Falco³  Alessandra Perrone³  Luigi Pio Guerrera⁴  Davide Ciardiello⁵ 

[1] Dermatology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy;Dipartimento di Biologia, Università degli Studi di Napoli “Federico II”, Napoli, Italy;Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80131, Napoli, Italy;Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania “Luigi Vanvitelli”, 80131, Napoli, Italy;Oncology Unit, Casa Sollievo della Sofferenza Hospital, 71013, San Giovanni Rotondo, Foggia, Italy;Oncology Unit, Casa Sollievo della Sofferenza Hospital, 71013, San Giovanni Rotondo, Foggia, Italy;

关键词: Metastatic melanoma;    Drug resistance;    BRAF and MEK inhibitors;    EMT transition;    EPH signaling;    DDR signaling, multikinase inhibitors, ALW‑II‑41‑27 inhibitor;   

DOI  :  10.1186/s41231-022-00133-5

 received in 2022-10-11, accepted in 2022-12-11,  发布年份 2022

来源: Springer

【 摘 要 】

The BRAF and MEK inhibitors combined strategies have dramatically changed the outcome of BRAF-mutated metastatic melanoma patients. However, despite the initial promising results, the onset of primary or acquired resistance occurs in nearly half of the patients at about one year from the diagnosis. Understanding the mechanisms of resistance to these inhibitors is therefore critical for planning more effective therapeutic strategies able to improve patient outcomes. To this aim we generated BRAF and MEK inhibitors resistant melanoma cells starting from the SAN and A375 lines, both harboring the most common BRAF-V600 mutation and sensitive to these drugs. The obtained double-resistant cell lines were characterized by MTT cell proliferation, migration, invasion assays, phosphoarray and western blot analysis. Here we report that the overexpression of several Tyrosine Kinase Receptors (TKRs), such as EphA2 and DDRs, drives the resistance to these drugs and that this resistance can be overcome by treatment with ALW‑II‑41‑27 multikinase inhibitor. ALW‑II‑41‑27 blocks not only TKRs expression, but also the related downstream AKT and MAPK signaling pathways and its efficacy is documented by decreased cell viability and reduced cell invasion/migration of the resistant cells. Our results can delineate a novel promising therapeutic approach to overcoming the drug resistance occurring in BRAF-mutated metastatic melanoma.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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