Coamplification of
            <i>miR-4728</i>
            protects
            <i>HER2</i>
            -amplified breast cancers from targeted therapy

Floros, Konstantinos V.; Lochmann, Timothy L.; Hu, Bin; Monterrubio, Carles; Hughes, Mark; Wells, Jason D.; Bernadó-Morales, Cristina; Ghotra, Maninderjit S.; Costa, Carlotta; Souers, Andrew J.; Boikos, Sosipatros A.; Leverson, Joel D.; Tan, Ming; Serra, Violeta; Koblinski, Jennifer E.; Arribas, Joaquı́n; Prat, Aleix; Paré, Laia; Miller, Todd W.; Dozmorov, Mikhail G.; Harada, Hisashi; Windle, Brad E.; Scaltriti, Maurizio; Faber, Anthony C.

doi:10.1073/pnas.1717820115

Cited by 25 publications

(30 citation statements)

References 72 publications

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“…To summarize, the phenomenon of intronic microRNAs to support the function of their host genes has already been described. 9 However, in our study, 10 we have found that a microRNA species which is co-amplified within the HER2 amplicon, and in this case the HER2 gene itself, mitigates the efficacy of HER2 inhibitors. With many other actionable cancer drivers activated by amplification, such as EGFR in Head and Neck cancers and colorectal cancers, a careful assessment of the other co-amplified genes may provide important mechanistic insights (and possibly biomarkers) for intrinsic resistance to the therapies directed against these cancer drivers.…”

contrasting

confidence: 51%

One gene to rule them all…and in the darkness bind them

Floros¹,

Faber

2018

Molecular & Cellular Oncology

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Pharmaceutical inhibition of the Human Epidermal growth factor Receptor 2 ( oncogene has dramatically improved outcomes in -amplified breast cancers. However, monotherapy HER2 inhibitors are not effective. We have recently reported that a co-amplified microRNA within the amplicon, leads to activation of the oncogene Myeloid Cell Leukemia-1 (), tempering cell death responses to HER2 inhibitors. Importantly, HER2 inhibitors are sensitized to cell death by the addition of pharmacological MCL-1 inhibitors, which are entering clinical trials.

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confidence: 51%

One gene to rule them all…and in the darkness bind them

Floros¹,

Faber

2018

Molecular & Cellular Oncology

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“…3 and 4), it was recently reported that MCL-1 levels increase in EGFRi-acquired resistant patients (52). In addition, recent studies have demonstrated a key role for MCL-1 in the survival of subsets of not only NSCLC (40), but also breast (42,53), neuroblastoma (25), and blood cancers (43). Although the protein levels of MCL-1 in DTCs were sharply upregulated (Fig.…”

Section: Discussionmentioning

confidence: 85%

Increased Synthesis of MCL-1 Protein Underlies Initial Survival of EGFR-Mutant Lung Cancer to EGFR Inhibitors and Provides a Novel Drug Target

Song

Hosono

Turner

et al. 2018

Clinical Cancer Research

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EGFR inhibitors (EGFRi) are effective against -mutant lung cancers. The efficacy of these drugs, however, is mitigated by the outgrowth of resistant cells, most often driven by a secondary acquired mutation in EGFR, We recently demonstrated that can arise during treatment; it follows that one potential therapeutic strategy to thwart resistance would be identifying and eliminating these cells [referred to as drug-tolerant cells (DTC)] prior to acquiring secondary mutations like We have developed DTCs to EGFRi in-mutant lung cancer cell lines. Subsequent analyses of DTCs included RNA-seq, high-content microscopy, and protein translational assays. Based on these results, we tested the ability of MCL-1 BH3 mimetics to combine with EGFR inhibitors to eliminate DTCs and shrink -mutant lung cancer tumors We demonstrate surviving-mutant lung cancer cells upregulate the antiapoptotic protein MCL-1 in response to short-term EGFRi treatment. Mechanistically, DTCs undergo a protein biosynthesis enrichment resulting in increased mTORC1-mediated mRNA translation of MCL-1, revealing a novel mechanism in which lung cancer cells adapt to short-term pressures of apoptosis-inducing kinase inhibitors. Moreover, MCL-1 is a key molecule governing the emergence of early -mutant DTCs to EGFRi, and we demonstrate it can be effectively cotargeted with clinically emerging MCL-1 inhibitors both and Altogether, these data reveal that this novel therapeutic combination may delay the acquisition of secondary mutations, therefore prolonging therapy efficacy..

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“…To this extent, Shin et al noticed a decreased expression of miR-16, miR-21 and miR-199a-5p along with an increase in the levels of miR-92a-3p and miR-342-3p in both blood and tissue samples collected from TNBC patients [188]. Meanwhile, in HER2+ tumors, it has repeatedly been shown that miR-4728 is co-expressed with HER2, acting as an oncogene [189][190][191]. Moreover, Søkilde et al have recently demonstrated the expression of two other small RNAs in HER2-enriched tumors, namely miR-2115 and miR-7158, which are otherwise very lowly expressed in healthy tissues [192].…”

Section: Mirnas In Distinguishing Cancer Subtypesmentioning

confidence: 99%

miRNAs as Biomarkers in Disease: Latest Findings Regarding Their Role in Diagnosis and Prognosis

Condrat

Thompson

Barbu

et al. 2020

Cells

843

583

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MicroRNAs (miRNAs) represent a class of small, non-coding RNAs with the main roles of regulating mRNA through its degradation and adjusting protein levels. In recent years, extraordinary progress has been made in terms of identifying the origin and exact functions of miRNA, focusing on their potential use in both the research and the clinical field. This review aims at improving the current understanding of these molecules and their applicability in the medical field. A thorough analysis of the literature consulting resources available in online databases such as NCBI, PubMed, Medline, ScienceDirect, and UpToDate was performed. There is promising evidence that in spite of the lack of standardized protocols regarding the use of miRNAs in current clinical practice, they constitute a reliable tool for future use. These molecules meet most of the required criteria for being an ideal biomarker, such as accessibility, high specificity, and sensitivity. Despite present limitations, miRNAs as biomarkers for various conditions remain an impressive research field. As current techniques evolve, we anticipate that miRNAs will become a routine approach in the development of personalized patient profiles, thus permitting more specific therapeutic interventions.Biogenesis of miRNA begins in the nucleus, where the transcription of its precursor, primary miRNA or pri-miRNA takes place under the influence of RNA polymerases II and III [11,12]. The resulting molecule is a hairpin-like structure, which contains a loop at one end [11]. This primordial mi-RNA precursor that is usually made up of hundreds of nucleotides is then processed consecutively by two RNase III enzymes [13][14][15]. The first enzyme to act upon the pri-miRNA, which still resides in the nucleus, is called Drosha or DCGR8, and turns it into a new hairpin-like structure of approximately 70 nucleotides, the Precursor-miRNA or pre-miRNA. The latter is then transported to the cytoplasm, with the help of Exportin-5, where it is cleaved again by the Ago2/Dicer complex leading to the short, mature miRNA double strands [16].Further on, one of the strands, usually known as the guide strand, will be integrated into the RNA-induced silencing complex (RISC), while the other one, known as the passenger strand, is going to be degraded, even though in some occasions it has been found to be also functional [17]. In most cases, the strand that contains the less stable 5 end or a uracil at the beginning is more likely to be selected as the guide strand [18][19][20]. In those situations, where the passenger strand is not degraded and both get incorporated into the miRISC complex, the mature miRNA in the guide strand will be the dominant one [21,22].The main role of miRNA in the human body is gene regulation [23] by mediating the degradation of mRNA and also by regulating transcription and translation through canonical and non-canonical mechanisms [4]. The canonical mechanism means that the miRISC complex containing the miRNA guide strand is exerting its action by binding to the targ...

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Coamplification of miR-4728 protects HER2 -amplified breast cancers from targeted therapy

Cited by 25 publications

References 72 publications

One gene to rule them all…and in the darkness bind them

One gene to rule them all…and in the darkness bind them

Increased Synthesis of MCL-1 Protein Underlies Initial Survival of EGFR-Mutant Lung Cancer to EGFR Inhibitors and Provides a Novel Drug Target

miRNAs as Biomarkers in Disease: Latest Findings Regarding Their Role in Diagnosis and Prognosis

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