MicroRNA‐Based Therapeutic Strategies for Targeting Mutant and Wild Type RAS in Cancer

Abstract

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 anti-sense 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 microRNAs. 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 in order 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).

Expression of human endogenous retrovirus-K is strongly associated with the basal-like breast cancer phenotype

“…Wild-type Ras is capable of promoting development of cancers 30 , including breast cancer 31 , and basal breast cancer in particular 21 32 . There is a large body of data supporting the concept that wild-type Ras plays a critical role in cells that harbor Ras mutations 33 . Using TCGA data, it has been reported that over 30% of basal-like breast cancers display KRAS gene amplifications 34 , and an increase in genomic DNA copy numbers at the KRAS2 locus was reported in 9 of 16 human basal-like tumors 35 .…”

Effects of MIR143 on rat sarcoma signaling networks in solid tumors: A brief overview

“…In 2005, MIRLET7 became the first tumor suppressive miRNA reported to downregulate RAS expression in lung tumors 27 . Later, numerous other miRNA were discovered to target RAS or its effector molecules in numerous cancers 28 . There are several miRNA reported to target KRAS other than MIRLET7 29 .…”

Role of miR-483 in digestive tract cancers: from basic research to clinical value

“…Furthermore, these agents may alter physiological processes or may break the organ system function due to the accumulation, clearance, and excretion of these molecules. Hence, to it is necessary to take these therapeutic barriers into consideration so as to utilize miRNA-based therapeutics successfully 65 . Although making miRNA replacement therapy routine is not an easy task, it should be noted that miRNAs were found in mammals just a decade ago.…”