Abstract
Hyperactive RAS/RAF/MEK/ERK signaling has a well-defined role in cancer biology. Targeting this pathway results in complete or partial regression of most cancers. In recent years, cancer genomic studies have revealed that genetic alterations that aberrantly activate the RAS/RAF/MEK/ERK signaling mainly occur on RAF or upstream, which motivated the extensive development of RAF inhibitors for cancer therapy. Currently, the first-generation RAF inhibitors have been approved for treating late-stage cancers with BRAF(V600E) mutations. Although these inhibitors have achieved promising outcomes in clinical treatments, their efficacy is abolished by quick-rising drug resistance. Moreover, cancers with hyperactive RAS exhibit intrinsic resistance to these drugs. To resolve these problems, the second-generation RAF inhibitors have been designed and are undergoing clinical evaluations. Here, we summarize the recent findings from mechanistic studies on RAF inhibitor resistance and discuss the critical issues in the development of next-generation RAF inhibitors with better therapeutic index, which may provide insights for improving targeted cancer therapy with RAF inhibitors.
Highlights
RAS/RAF/MEK/ERK signaling plays a determinant role in cell fate and is tightly regulated in normal cells[1,2,3]
The majority of genetic alterations that aberrantly activate this pathway occur on receptor tyrosine kinases (RTKs), neurofibromatosis type 1 (NF1), RAS, and RAF[8,9,10]
Oncogenic RTK alterations can be effectively targeted by tyrosine kinase inhibitors (TKIs) or neutralizing antibodies[11,12,13,14], while active RAS mutations except ~10% G12C have been thought as “undruggable” targets[15,16]
Summary
RAS/RAF/MEK/ERK signaling plays a determinant role in cell fate and is tightly regulated in normal cells[1,2,3]. [76,180,181] On the other hand, RO5126766, a RAF/MEK dual inhibitor that docks onto the RAF/MEK interface but prevents conformational alteration of the RAF/MEK complex, blocks the MEK phosphorylation by RAF as trametinib does[182] This allosteric inhibitor has exhibited promising activity against various cancers harboring RAS mutations in Phase I clinical trials[183,184,185]. In contrast to RO5126766, trametiglue has orders of magnitude higher potency and much slower off-rate kinetics, which results in better long-term inhibitory activity on both BRAF- and RAS-mutated tumors, its clinical efficacy needs further evaluation These allosteric RAF inhibitors that target RAF/RAF or RAF/MEK interfaces without altering R-spine upon engagement could have higher efficacies against cancers harboring R-spine-stabilized RAF mutants, they have not been tested on such cancers yet. The high-resolution structures of RAF proteins and RAF/MEK complexes resolved in recent years[21,29,64,84,85,94,186] make possible in silico investigation of such allosteric sites and will accelerate the development of RAF inhibitors, isoform-specific inhibitors through computationaided molecular docking and optimization
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