MicroRNA-Based Therapeutic Strategies for Targeting Mutant and Wild Type RAS in Cancer.
MicroRNAs (miRs) have been causally implicated in the progression and development of a wide variety of cancers. miRs modulate the activity of key cell signaling networks by regulating the translation of pathway component proteins. Thus, the pharmacological targeting of miRs that regulate cancer cell signaling networks, either by promoting (using miR-supplementation) or by suppressing (using antisense oligonucleotide-based strategies) miR activity is an area of intense research. The RAS-extracellular signal regulated kinase (ERK) pathway represents a major miR-regulated signaling network that endows cells with some of the classical hallmarks of cancer, and is often inappropriately activated in malignancies by somatic genetic alteration through point mutation or alteration of gene copy number. In addition, recent progress indicates that many tumors may be deficient in GTPase activating proteins (GAPs) due to the collaborative action of oncogenic miRs. Recent studies also suggest that in tumors harboring a mutant RAS allele there is a critical role for wild type RAS proteins in determining overall RAS-ERK pathway activity. Together, these two advances comprise a new opportunity for therapeutic intervention. In this review, we evaluate miR-based therapeutic strategies for modulating RAS-ERK signaling in cancers; in particular for more direct modulation of RAS-GTP levels, with the potential to complement current strategies to yield more durable treatment responses. To this end, we discuss the potential for miR-based therapies focused on three prominent miRs including the pan-RAS regulator let-7 and the GAP regulator comprised of miR-206 and miR-21 (miR-206/21).
Department of Biochemistry, West Virginia University, Morgantown, WV, 26506, USA.|Program in Cancer Cell Biology, West Virginia University, Morgantown, WV, 26506, USA.
Sriganesh B
SB
Sharma
Department of Biochemistry, West Virginia University, Morgantown, WV, 26506, USA.|The Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV, 26506, USA.
John Michael
JM
Ruppert
D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
D035683:MicroRNAs; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins
RAS-GTP; RAS-extracellular signal regulated kinase signaling; cancer; microRNAs