Cancer resistance to therapies against the EGFR-RAS-RAF pathway: The role of MEK. (February 2017)

• Record Type: Journal Article
• Authors: Martinelli, Erika; Morgillo, Floriana; Troiani, Teresa; Ciardiello, Fortunato
• Is Part Of: Cancer treatment reviews. Volume 53(2017)
• Page Start: 61
• Page End: 69
• Publication Date: 2017-02
• Subjects: MEK -- Resistance -- NSCLC -- CRC; Cancer -- Periodicals; Cancer -- Treatment -- Periodicals; Neoplasms -- therapy -- Periodicals; Cancer -- Périodiques; Cancer -- Traitement -- Périodiques; Cancer -- Treatment; Electronic journals; Periodicals; 616.99406
• DOI: 10.1016/j.ctrv.2016.12.001
• Languages: English
• ISSNs: 0305-7372

Abstract

Highlights: MEK1/2 is a transducer of RAS-RAF-MAPK signalling cascade with a role in cancers. New drugs targeting MEK1/2 have been developed, particularly for RAS mutant tumours. MEK inhibitors display a modest single agent activity. No other biomarkers than BRAF mutations predict the sensitivity to MEK inhibitors. MEK activation is described in resistance to targeted agents used in CRC and NSCLC. Abstract: The mitogen-activated protein kinases (MAPKs) mediate intracellular signals activated by a wide variety of extracellular stimuli. The activation of the RAS-RAF-MEK-MAPK cascade culminates in the regulation of gene transcription promoting cancer cell proliferation, survival, migration and angiogenesis. MEK (mitogen-activated protein kinase kinase-MAPKK) 1/2 is a transducer of the growth factor receptor-RAS-RAF-MAPK signalling cascade and plays a relevant role in development and progression of human cancers, such as colorectal cancer (CRC), non small cell lung cancer (NSCLC). Direct inhibition of MEK is a promising strategy and several inhibitors are currently under evaluation in clinical trials showing initial clinical activity in different tumours. MEK activation, by different genetic mechanisms, has been described for both intrinsic and acquired resistance to drugs targeting the EGFR (Epidermal Growth Factor Receptor)-RAS-RAF pathway in CRC, NSCLC. Combination therapies with chemotherapy and/or with molecular targeted agents are warranted and biomarkers studies are needed to identify those tumours dependent on MEK signalling.