期刊
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
卷 9, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2021.647311
关键词
MAPK; ERK1; 2; 5; resistance mechanisms; combined therapy; targeted therapy; cancer
资金
- Associazione Italiana per la Ricerca sul Cancro, AIRC [IG-15282, IG-21349]
- Ente Fondazione Cassa di Risparmio di Firenze (ECRF)
- Universita degli Studi di Firenze (Fondo di Ateneo ex-60%)
- Carlo Zanotti FIRC-AIRC fellowship [23847]
Molecularly tailored therapies have revolutionized cancer treatment, yet resistance mechanisms remain a major obstacle. The activation of the MEK5-ERK5 pathway as a resistance mechanism to RAF-MEK1/2-ERK1/2 inhibitors is discussed, emphasizing the need for the development of additional MEK5-ERK5 inhibitors to prevent resistance to cancer therapies.
Molecularly tailored therapies have opened a new era, chronic myeloid leukemia being the ideal example, in the treatment of cancer. However, available therapeutic options are still unsatisfactory in many types of cancer, and often fail due to the occurrence of resistance mechanisms. With regard to small-molecule compounds targeting the components of the Mitogen-Activated Protein Kinase (MAPK) cascade RAF-MEK1/2-ERK1/2, these drugs may result ineffective as a consequence of the activation of compensatory pro-survival/proliferative signals, including receptor tyrosine kinases, PI3K, as well as other components of the MAPK family such as TPL2/COT. The MAPK ERK5 has been identified as a key signaling molecule in the biology of several types of cancer. In this review, we report pieces of evidence regarding the activation of the MEK5-ERK5 pathway as a resistance mechanism to RAF-MEK1/2-ERK1/2 inhibitors. We also highlight the known and possible mechanisms underlying the cross-talks between the ERK1/2 and the ERK5 pathways, the characterization of which is of great importance to maximize, in the future, the impact of RAF-MEK1/2-ERK1/2 targeting. Finally, we emphasize the need of developing additional therapeutically relevant MEK5-ERK5 inhibitors to be used for combined treatments, thus preventing the onset of resistance to cancer therapies relying on RAF-MEK1/2-ERK1/2 inhibitors.
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