We use cookies to understand how you use our site and to improve your experience. This includes personalizing content and advertising. To learn more, click here. By continuing to use our site, you accept our use of cookies. Cookie Policy.

Features Partner Sites Information LinkXpress hp
Sign In
Advertise with Us
LGC Clinical Diagnostics

Download Mobile App




Targeting MicroRNA Blocks Drug Tolerance in Some Cancers

By LabMedica International staff writers
Posted on 15 Apr 2019
Print article
Image: A diagram of the epidermal growth factor receptor (EGFR) (rainbow colored, N-terminus = blue, C-terminus = red) complexed its ligand epidermal growth factor (magenta) (Photo courtesy of Wikimedia Commons).
Image: A diagram of the epidermal growth factor receptor (EGFR) (rainbow colored, N-terminus = blue, C-terminus = red) complexed its ligand epidermal growth factor (magenta) (Photo courtesy of Wikimedia Commons).
Cancer researchers have suggested that by exploiting the link between a specific microRNA and the tricarboxylic acid energy-producing cycle it may be possible to prevent or reverse the development of drug tolerance or resistance by non-small-cell lung carcinomas.

MicroRNAs (miRNAs) and short interfering RNAs (siRNA) comprise a class of about 20 nucleotides-long RNA fragments that block gene expression by attaching to molecules of messenger RNA in a fashion that prevents them from transmitting the protein synthesizing instructions they had received from the DNA. MiRNAs resemble siRNAs of the RNA interference (RNAi) pathway, except miRNAs derive from regions of RNA transcripts that fold back on themselves to form short hairpins, whereas siRNAs derive from longer regions of double-stranded RNA. With their capacity to fine-tune protein expression via sequence-specific interactions, miRNAs help regulate cell maintenance and differentiation.

Non-small cell lung cancers, which comprise about 85% of lung cancer diagnoses, tend to be less aggressive but harder to treat than small cell lung cancers. About 10% of non-small-cell lung carcinomas carry an epidermal growth factor receptor (EGFR) mutation. Drug tolerance developed by cancer cells is an acute defense response preceding a fully drug-resistant state and tumor relapse; however, there are few therapeutic agents targeting drug tolerance in the clinic.

As part of their effort to identify drugs able to modify drug tolerance, investigators at Beth Israel Deaconess Medical Center (Boston, MA, USA) found that the microRNA miR-147b initiated a reversible state of tolerance to the epidermal growth factor receptor (EGFR) inhibitor osimertinib in non-small-cell lung cancer. Osimertinib is a medication used to treat non-small-cell lung carcinomas with the specific EGFR mutation. It is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor.

The investigators reported in the April 8, 2019, online edition of the journal Nature Metabolism that using miRNA-seq analysis, they determined that miR-147b was the most upregulated microRNA in osimertinib-tolerant and EGFR-mutated lung cancer cells. Whole-transcriptome analysis of single-cell-derived clones revealed a link between osimertinib tolerance and pseudohypoxia responses irrespective of oxygen levels.

Further metabolomics and genetic studies demonstrated that osimertinib tolerance was driven by miR-147b-mediated repression of VHL (von Hippel-Lindau tumor suppressor) and succinate dehydrogenase, which are linked to the tricarboxylic acid energy-producing cycle and pseudohypoxia pathways. Finally, pretreatment with a miR-147b inhibitor delayed osimertinib-associated drug tolerance in patient-derived three-dimensional structures.

"These results were a surprise and represent a total novel finding in the area," said senior author Dr. Frank J. Slack, professor of medical research at Beth Israel Deaconess Medical Center. "In this study, we discovered that a microRNA known as miR-147b is a critical mediator of resistance among a subpopulation of tumor cells that adopt a tolerance strategy to defend against EGFR-based anticancer treatments. We are currently testing the idea of targeting this new pathway as a therapy in clinically relevant mouse models of EGFR-mutant lung cancer."

Related Links:
Beth Israel Deaconess Medical Center

New
Platinum Member
Flu SARS-CoV-2 Combo Test
OSOM® Flu SARS-CoV-2 Combo Test
Magnetic Bead Separation Modules
MAG and HEATMAG
Complement 3 (C3) Test
GPP-100 C3 Kit
Gold Member
TORCH Panel Rapid Test
Rapid TORCH Panel Test

Print article
77 ELEKTRONIKA

Channels

Clinical Chemistry

view channel
Image: PhD student and first author Tarek Eissa has analyzed thousands of molecular fingerprints (Photo courtesy of Thorsten Naeser / MPQ / Attoworld)

Screening Tool Detects Multiple Health Conditions from Single Blood Drop

Infrared spectroscopy, a method using infrared light to study the molecular composition of substances, has been a foundational tool in chemistry for decades, functioning similarly to a molecular fingerprinting... Read more

Hematology

view channel
Image: The Truvian diagnostic platform combines clinical chemistry, immunoassay and hematology testing in a single run (Photo courtesy of Truvian Health)

Automated Benchtop System to Bring Blood Testing To Anyone, Anywhere

Almost all medical decisions are dependent upon laboratory test results, which are essential for disease prevention and the management of chronic illnesses. However, routine blood testing remains limited worldwide.... Read more

Microbiology

view channel
Image: The Simplexa C. auris direct kit is a real-time polymerase chain reaction assay run on the LIAISON MDX instrument (Photo courtesy of Diasorin)

Novel Molecular Test to Help Prevent and Control Multi Drug-Resistant Fungal Pathogen in Healthcare Settings

Candida auris (C. auris) is a rapidly emerging multi drug-resistant fungal pathogen that is commonly found in healthcare environments, where it presents a challenge due to its ability to asymptomatically... Read more

Pathology

view channel
Image: The tool can improve precision oncology by accurately predicting molecular subtypes and therapy responses (Photo courtesy of Shutterstock)

Computational Tool Integrates Transcriptomic Data for Improved Breast Cancer Diagnosis and Treatment

Breast cancer is the most commonly diagnosed cancer globally, presenting in various subtypes that require precise identification for effective, personalized treatment. Traditionally, cancer subtyping has... Read more

Industry

view channel
Image: Beckman Coulter will utilize the ALZpath pTau217 antibody to detect key biomarker for Alzheimer\'s disease on its DxI 9000 immunoassay analyzer (Photo courtesy of Beckman Coulter)

Beckman Coulter Licenses Alzpath's Proprietary P-tau 217 Antibody to Develop Alzheimer's Blood Test

Cognitive assessments have traditionally been the primary method for diagnosing Alzheimer’s disease, but this approach has its limitations as symptoms become apparent only after significant brain changes... Read more
Copyright © 2000-2024 Globetech Media. All rights reserved.