Inhibiting drivers of non-mutational drug tolerance is a salvage strategy for targeted melanoma therapy.
Girotti, Maria Romina
AffiliationManchester Cancer Research Centre, Wellcome Trust Centre for Cell-Matrix Research, The University of Manchester, Michael Smith Building, Oxford Road, Manchester,
MetadataShow full item record
AbstractOnce melanomas have progressed with acquired resistance to mitogen-activated protein kinase (MAPK)-targeted therapy, mutational heterogeneity presents a major challenge. We therefore examined the therapy phase before acquired resistance had developed and discovered the melanoma survival oncogene MITF as a driver of an early non-mutational and reversible drug-tolerance state, which is induced by PAX3-mediated upregulation of MITF. A drug-repositioning screen identified the HIV1-protease inhibitor nelfinavir as potent suppressor of PAX3 and MITF expression. Nelfinavir profoundly sensitizes BRAF and NRAS mutant melanoma cells to MAPK-pathway inhibitors. Moreover, nelfinavir is effective in BRAF and NRAS mutant melanoma cells isolated from patients progressed on MAPK inhibitor (MAPKi) therapy and in BRAF/NRAS/PTEN mutant tumors. We demonstrate that inhibiting a driver of MAPKi-induced drug tolerance could improve current approaches of targeted melanoma therapy.
CitationInhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy. 2016, 29 (3):270-84 Cancer Cell
- Mitogen-activated protein kinase (MAPK) hyperactivation and enhanced NRAS expression drive acquired vemurafenib resistance in V600E BRAF melanoma cells.
- Authors: Lidsky M, Antoun G, Speicher P, Adams B, Turley R, Augustine C, Tyler D, Ali-Osman F
- Issue date: 2014 Oct 3
- HIV Drug to Aid Melanoma Therapies?
- Authors: Kim H, Ronai ZA
- Issue date: 2016 Mar 14
- Co-existence of BRAF and NRAS driver mutations in the same melanoma cells results in heterogeneity of targeted therapy resistance.
- Authors: Raaijmakers MI, Widmer DS, Narechania A, Eichhoff O, Freiberger SN, Wenzina J, Cheng PF, Mihic-Probst D, Desalle R, Dummer R, Levesque MP
- Issue date: 2016 Nov 22
- P53 and MITF/Bcl-2 identified as key pathways in the acquired resistance of NRAS-mutant melanoma to MEK inhibition.
- Authors: Najem A, Krayem M, Salès F, Hussein N, Badran B, Robert C, Awada A, Journe F, Ghanem GE
- Issue date: 2017 Sep
- Overcoming MITF-conferred drug resistance through dual AURKA/MAPK targeting in human melanoma cells.
- Authors: Pathria G, Garg B, Borgdorff V, Garg K, Wagner C, Superti-Furga G, Wagner SN
- Issue date: 2016 Mar 10