Saturday, August 16, 2014

eIF4F, the way to break resistance to anti-BRAF and anti-MEK in the future?

eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies   Boussemart, et al.  Nature. 2014. July.


'In BRAF (V600)-mutant tumors, the resistance to the drugs that targets BRAF or MEK kinases rely on reactivation of the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal pathway, on activation of the other PI(3)K-AKT-mTOR pathway, or on modulation of the caspase-dependent apoptotic cascade.  (WOW!!  But, basically - these three different 'pathways' can mess up a patient's response to BRAFi or MEKi treatment.)  All three of these pathways converge to regulate the formation of the eIF4F...complex, which binds to the...end of messenger RNA, thereby modulating the transcription of mRNAs...[and in this study they show] that the persistent formation of the eIF4F associated with resistance to anti-BRAF, anti-MEK, and anti-BRAF plus anti-MEK drug combinations in BRAF (V600)-mutant melanoma, colon, and thyroid cancer cell lines.  (Sooo, these smart peeps figured out the three main ways the eIF4F complex messes up the works.) [They developed a way to detect such interactions and showed] that the eIF4F complex formation is decreased in tumors that respond to anti-BRAF therapy and increased in resistant metastases... Strikingly, inhibiting the eIF4F complex...synergizes with [BRAFi] to kill the cancer cells.  eIF4f not only  appears to be an indicator of both innate and acquired resistance but also is a promising therapeutic target.  Combinations of drugs targeting BRAF (and/or MEK) and eIF4F may overcome most of the resistance mechanisms arising in BRAF(V600)-mutant cancers.'

Now...this is only in a petri dish, not demonstrated in humans...and therefore is a long way from use in peeps...but it certainly sounds promising to me!!!  Way to go, smart researcher people!! - c

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