reversing melanoma cross-resistance to braf and mek inhibitors by co-targeting the aktmtor pathway扭转黑色素瘤抗力移转braf和mek抑制剂co-targeting aktmtor通路.pdfVIP

Reversing Melanoma Cross-Resistance to BRAF and MEK Inhibitors by Co-Targeting the AKT/mTOR Pathway 1. 1. 1 1 1 2 Mohammad Atefi , Erika von Euw , Narsis Attar , Charles Ng , Connie Chu , Deliang Guo , Ramin 3 1 1,4 4,5 2,4 Nazarian , Bartosz Chmielowski , John A. Glaspy , Begonya Comin-Anduix , Paul S. Mischel , Roger S. Lo3,4, Antoni Ribas1,4,5* 1 Department of Medicine, Division of Hematology/Oncology, University of California Los Angeles, Los Angeles, California, United States of America, 2 Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California, United States of America, 3 Department of Medicine, Division of Dermatology, University of California Los Angeles, Los Angeles, California, United States of America, 4 Department of Surgery, Division of Surgical Oncology, University of California Los Angeles, Los Angeles, California, United States of America, 5 Jonsson Comprehensive Cancer Center at University of California Los Angeles, Los Angeles, California, United States of America Abstract Background: The sustained clinical activity of the BRAF inhibitor vemurafenib (PLX4032/RG7204) in patients with BRAFV600 mutant melanoma is limited primarily by the development of acquired resistance leading to tumor progression. Clinical trials are in progress using MEK inhibitors following disease progression in patients receiving BRAF inhibitors. However, the PI3K/AKT pathway can also induce resistance to the inhibitors of MAPK pathway. Methodology/Principal Findings: The sensi