Untying the gordion knot of targeting MET in cancer. (May 2018)

• Record Type: Journal Article
• Authors: Raghav, Kanwal; Bailey, Ann Marie; Loree, Jonathan M.; Kopetz, Scott; Holla, Vijaykumar; Yap, Timothy Anthony; Wang, Fang; Chen, Ken; Salgia, Ravi; Hong, David
• Is Part Of: Cancer treatment reviews. Volume 66(2018)
• Page Start: 95
• Page End: 103
• Publication Date: 2018-05
• Subjects: Amplification -- Cancer -- MET -- Mutation -- Targeted therapy; 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.2018.04.008
• Languages: English
• ISSNs: 0305-7372

Abstract

Highlights: Aberrant MET signaling promotes tumor growth, invasion, metastasis and survival. Activated MET pathway is implicated in acquired resistance to targeted therapies. Early trials targeting MET failed due to poor biomarker and patient selection. MET amplification and mutation are evolving as predictors for MET inhibition. Trials using novel MET inhibitors in biomarker selected population are needed. Abstract: Despite compelling evidence backing the crucial role of a dysregulated MET axis in cancer and a myriad of agents targeting this pathway in active clinical development, the therapeutic value of MET inhibition in cancer oncology remains to be established. Although a series of disappointing clinical trials, at first, lessened fervor for targeting this pathway, investigations continue unabated with a number of novel active compounds entering clinical trials. Suboptimal designs which lacked biomarker selection have been the main reason for these early failures and this has stimulated a more biomarker enriched approach lately. Fresh insights into the mechanics of diverse MET aberrations (amplifications and mutations) have allowed trial enrichment for appropriate patients in appropriate disease settings. Development of MET inhibition as a therapeutic strategy in cancer has been a lesson in itself reflecting the challenging opportunities enclosed in the genetic landscape of cancer. Here, we will review the status of MET targeted therapy in development as it stands today, discuss emerging paradigms in MET inhibition and theorize on concepts for future development. We venture to propose that in spite of early disappointments, the future of this therapeutic strategy is promising with use of appropriate predictive biomarker in the right clinical context.