KANAZAWA, Japan, Sept. 16, 2020 /PRNewswire/ -- Researchers at Kanazawa University report in Nature Communications the mechanism making some lung-cancer patients resistant to the drug osimertinib. In addition, they suggest a combined drug treatment resolving osimertinib resistance in the case of cancer cells expressing low amounts of AXL, a protein belonging to the class of receptor tyrosine kinases.
The effectiveness of cancer treatment is often hampered by cancer cells being heterogeneous. This is the case for EGFR-mutated lung cancer: drugs based on biomolecules of a type known as tyrosine kinase inhibitor (TKI) have been used to treat the disease, but with various levels of efficacy. (EGFR stands for "epidermal growth factor receptor", a protein playing an important role in signaling processes from the extracellular environment to a cell.) Sometimes, tumor cells are simply resistant to the drug. Now, Seiji Yano from Kanazawa University and colleagues have investigated the efficacy of the TKI osimertinib for treating EGFR-mutated lung cancer, and how it relates to the expression in tumor cells of a particular protein called AXL. They found that both AXL-high and -low expressing tumor cells showed tolerance (acquired resistance) to osimertinib, but that the mechanisms involved are different for the two situations. Moreover, the researchers suggest a way to enhance the success of osimertinib treatment for the case of AXL-low expressing tumors.
First, the scientists compared the susceptibility to osimertinib in both AXL-high and -low expressing tumor cells in in vitro experiments. They observed that osimertinib inhibited the viability of the cancer cells in both cases, but that the sensitivity to the drug was higher for AXL-low expressing EGFR-mutated lung cancer cells.They also noticed that a small number of tumor cells survived the procedure an indication of osimertinib tolerance.These findings were consistent with results from the clinical study of the drug performed earlier on 29 patients with EGFR-mutated non-small cell lung cancer.
Through experiments aiming to understand the mechanism behind osimertinib tolerance, Yano and colleagues discovered that phosphorylation of IGF-1R was increased in AXL-low-expressing tumor cell lines, but not in AXL-high expressing tumors. (IGF-1R stands for 'insulin-like growth factor 1 receptor'; it is a protein located on the surface of human cells. Phosphorylation is the chemical process of adding a phosphoryl group.) The researchers then found that phosphorylated IGF-1R supported the survival of AXL-low expressing tumors after exposure to osimertinib.
The scientists then tested whether the observed osimertinib resistance could be resolved by administering linsitinib, a substance known to inhibit the phosphorylation of IGF-1R. Encouraged by the positive outcome of the experiment, Yano and colleagues went further and evaluated the combination of osimertinib and linsitinib. Their conclusion was that the transient combination of linsitinib with continuous osimertinib treatment could cure or at least dramatically delay tumor recurrence in AXL-low-expressing EGFR-mutated lung cancer. More investigating needs to be done, though. Quoting the researchers: " the safety and efficacy of the transient combination of IGF-1R inhibitor and osimertinib should be evaluated in the clinical trials."
Background
Tyrosine kinase inhibitors
A tyrosine kinase inhibitor is a drug inhibiting (that is, preventing or reducing the activity of) a specific tyrosine kinase. A tyrosine kinase is a protein (enzyme) involved in the activation of other proteins by signaling cascades. The activation happens by the addition of a phosphate group to the protein (phosphorylation); it is this step that a tyrosine kinase inhibitor inhibits. Tyrosine kinase inhibitors are used as anticancer drugs. One such drug is osimertinib, used to treat EGFR-mutated lung cancer.
AXL
AXL is a receptor tyrosine kinase a tyrosine kinase consisting of an extracellular part, a transmembrane part ('sitting' within a cell membrane) and an intracellular part. AXL regulates various important cellular processes, including proliferation, survival and motility.
In recent years, it has become clear that AXL is a key facilitator of drug tolerance by cancer cells. Seiji Yano from Kanazawa University and colleagues have found that this is also the case for EGFR-mutated lung cancer. While a high expression of AXL correlates with resistance to osimertinib, such tolerance also occurs in AXL-low-expressing cancer cells. Yano and colleagues have now found that for the latter case, phosphorylation of IGF-1R (insulin-like growth factor 1 receptor) is responsible for the resistance to osimertinib.
Reference
Rong Wang, Tadaaki Yamada, Kenji Kita, Hirokazu Taniguchi, Sachiko Arai, Koji Fukuda, Minoru Terashima, Akihiko Ishimura, Akihiro Nishiyama, Azusa Tanimoto, Shinji Takeuchi, Koshiro Ohtsubo, Kaname Yamashita, Tomoyoshi Yamano, Akihiro Yoshimura, Koichi Takayama, Kyoichi Kaira, Yoshihiko Taniguchi, Shinji Atagi, Hisanori Uehara, Rikinari Hanayama, Isao Matsumoto, Xujun Han, Kunio Matsumoto, Wei Wang, Takeshi Suzuki, and Seiji Yano. Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer, Nature Communications 11, XX(2020).
DOI: 10.1038/s41467-020-18442-4
URL: https://doi.org/10.1038/s41467-020-18442-4
Link to figure https://nanolsi.kanazawa-u.ac.jp/wp-content/uploads/2020/09/Figure-768x567.png
Figure CaptionMechanism of targeted drugs tolerance in lung cancer cells
Further information
About WPI NanoLSI Kanazawa University Hiroe YonedaVice Director of Public AffairsWPI Nano Life Science Institute (WPI-NanoLSI)Kanazawa UniversityKakuma-machi, Kanazawa 920-1192, JapanEmail: [emailprotected]Tel: +81 (76) 234-4550
About Nano Life Science Institute (WPI-NanoLSI) https://nanolsi.kanazawa-u.ac.jp/en/
Nano Life Science Institute (NanoLSI), Kanazawa University is a research center established in 2017 as part of the World Premier International Research Center Initiative of the Ministry of Education, Culture, Sports, Science and Technology. The objective of this initiative is to form world-tier research centers. NanoLSI combines the foremost knowledge of bio-scanning probe microscopy to establish 'nano-endoscopic techniques' to directly image, analyze, and manipulate biomolecules for insights into mechanisms governing life phenomena such as diseases.
About Kanazawa Universityhttp://www.kanazawa-u.ac.jp/e/
As the leading comprehensive university on the Sea of Japan coast, Kanazawa University has contributed greatly to higher education and academic research in Japan since it was founded in 1949. The University has three colleges and 17 schools offering courses in subjects that include medicine, computer engineering, and humanities.
The University is located on the coast of the Sea of Japan in Kanazawa a city rich in history and culture. The city of Kanazawa has a highly respected intellectual profile since the time of the fiefdom (1598-1867). Kanazawa University is divided into two main campuses: Kakuma and Takaramachi for its approximately 10,200 students including 600 from overseas.
SOURCE Kanazawa University
Read the rest here:
- Twitter Working on Plan to Charge Users to Watch Videos - November 4th, 2022
- Manslaughter Case Has a Strange Twist: Tesla That Killed Couple Was on Autopilot - November 4th, 2022
- Greta Thunberg Says UN Climate Conference Is a Scam and She's Not Attending - November 4th, 2022
- There's Something Strange About How These Stars Are Moving, Scientists Say - November 4th, 2022
- This Deepfake AI Singing Dolly Parton's "Jolene" Is Worryingly Good - November 4th, 2022
- NASA Sets Launch Date for Mission to $10 Quintillion Asteroid - November 4th, 2022
- Huge Drone Swarm to Form Giant Advertisement Over NYC Skyline - November 4th, 2022
- China Plans to Send Monkeys to Space Station to Have Sex With Each Other - November 4th, 2022
- Jeff Bezos' Housekeeper Says She Had to Climb Out the Window to Use the Bathroom - November 4th, 2022
- AOC Says Her Twitter Account Broke After She Made Fun of Elon Musk - November 4th, 2022
- Scientists Use Actual Lunar Soil Sample to Create Rocket Fuel - November 4th, 2022
- Chinese Spaceplane Releases Mystery Object Into Orbit - November 4th, 2022
- Cats May Be Tampering With Crime Scenes, Scientists Say - November 4th, 2022
- Hackers Just Took Down One of the World's Most Advanced Telescopes - November 4th, 2022
- Elon Musk Meeting With Advertisers, Begging Them Not to Leave Twitter - November 4th, 2022
- That "Research" About How Smartphones Are Causing Deformed Human Bodies Is SEO Spam, You Idiots - November 4th, 2022
- Scientists Found a Way to Control How High Mice Got on Cocaine - November 4th, 2022
- Scientists Spot "Stripped, Pulsating Core" of Star Caused By Horrific Accident - November 4th, 2022
- US Gov to Crack Down on "Bossware" That Spies On Employees' Computers - November 4th, 2022
- Micro and Nano Engineering - Journal - Elsevier - June 29th, 2022
- Arduino Nano Library for Proteus - The Engineering Projects - June 29th, 2022
- People | Centre for Nano Science and Engineering (CeNSE), IISc - June 29th, 2022
- Forge Nano and Anovion Partner to Help Propel US Battery Tech and Strengthen Domestic Supply Chain - GlobeNewswire - June 29th, 2022
- Stanford engineers' optical concentrator could help solar arrays capture more light even on a cloudy day without tracking the Sun - EurekAlert - June 29th, 2022
- Nanotechnology Market 2022 Detailed Analysis Of Current Industry Demand with Forecasts Growth by 2028 Designer Women - Designer Women - June 29th, 2022
- Why is the Weebit Nano share price charging 5% higher today? - The Motley Fool Australia - June 29th, 2022
- Determining Ways to Combine the Power Conversion and Storage Capacity Needs of Solar Energy Into One Device - AZoCleantech - June 29th, 2022
- New method based on smart materials for experimenting with cells - Nanowerk - June 29th, 2022
- The Ecosystem: leather is so over, but what comes next? - Science Business - June 29th, 2022
- Aalto University scoops 18M in Academy of Finland research funding - Science Business - June 29th, 2022
- 50 Percent of Women in STEM Careers Ready to Join Great Resignation in New Gotara REACH Report - PR Web - June 29th, 2022
- Meet our Sustainability Awards Jury & see what they think about the 2022 program - Architecture and Design - June 29th, 2022
- Announcing Six Winners of the Third Annual Manning/IALS Innovation Awards : Institute for Applied Life Sciences - UMass News and Media Relations - November 13th, 2021
- Lecturer Positions in Intelligent Systems Engineering job with Indiana University Bloomington / Luddy School of Informatics, Computing, and... - November 13th, 2021
- Pressure BioSciences Awarded Second U.S. Patent for Its Revolutionary Ultra Shear Technology Platform, for Its Innovative NanoGap Valve - Yahoo... - November 13th, 2021
- Novel Imaging Technique Takes High Resolution 3D Images of Cells - AZoNano - November 13th, 2021
- "Dialogues between world Laureates and Gen-Z" was successfully held: an event focusing on Gen Z and the future of Science - PRNewswire - November 13th, 2021
- NVIDIA Announces Jetson AGX Orin: Modules and Dev Kits Coming In Q1'22 - AnandTech - November 13th, 2021
- Research on Food and Beverage Air Filtration Market Key Data Points Necessary for Effective Strategies | 3M, APC Filtration, Camfil Group, Donaldson... - November 13th, 2021
- Scientists invent 'smart' window material that blocks rays without blocking views - Nanowerk - November 13th, 2021
- How can Australia get cracking on emissions? The know-how we need is in our universities - The Conversation AU - November 13th, 2021
- Machine learning links material composition and performance in catalysts - Nanowerk - August 24th, 2021
- What Is Nanotechnology And How Is It Impacting Neuroscience? - Forbes - August 24th, 2021
- Could Nanotechnology Help to End the Fight Against COVID-19? | IJN - Dove Medical Press - August 24th, 2021
- Are Radioactive Diamond Batteries the Solution to Nuclear Waste? - Interesting Engineering - August 24th, 2021
- Updating the PLOS ONE Nanomaterials Collection Author Perspectives, Part 2 - EveryONE - PLoS Blogs - August 24th, 2021
- Scientists Develop Woven Nanotube Fibers Capable of Converting Heat into Energy - AZoNano - August 24th, 2021
- This engineer is searching for signs of life in the clouds of Venus - Create - create digital - August 24th, 2021
- Ultra-Low IQ PMIC from ROHM Selected to Power NXP iMX8M Nano for High Performance Embedded Artists Industrial Control Board - EE Journal - February 20th, 2021
- Perseverance touches down on Mars and Jaguar going electric: 10 top stories of the week - Professional Engineering - February 20th, 2021
- mHealth Wearable Boosts Remote Patient Monitoring, Connected Health - mHealthIntelligence.com - February 20th, 2021
- New Skin Patch Brings Us Closer to Wearable, All-In-One Health Monitor - I-Connect007 - February 20th, 2021
- Next: Superconducting nanowires could be used in circuits - Electronics Weekly - February 20th, 2021
- 4 UCSD Researchers Win Sloan Research Fellowships for Early Career Scientists - Times of San Diego - February 20th, 2021
- Pendse named 2021 Distinguished Maine Professor - UMaine News - University of Maine - University of Maine - February 20th, 2021
- New Polymer Cores Added to Windows Could Solve Energy Issues for Buildings - AZoBuild - February 20th, 2021
- Caltech Professor Inducted into the National Academy of Engineering Pasadena Now - Pasadena Now - February 15th, 2021
- How Nanotechnology Has Improved the Auto Industry - Salon Priv Magazine - February 15th, 2021
- Caltech: Tai Inducted into the National Academy of Engineering - India Education Diary - February 15th, 2021
- Plastic-nanotube composite 'tougher and lighter than similar forms of aluminium' - Professional Engineering - February 15th, 2021
- New coalmine questioned and high-density hydro planned: 10 top stories of the week - Professional Engineering - February 15th, 2021
- Scientists study moving worm "blobs" to create robot swarms - Big Think - February 15th, 2021
- Riding the Funding Wave: These DFW Startups Got the Money in 2020 Dallas Innovates - dallasinnovates.com - February 15th, 2021
- UVA Honors Distinguished Researchers at Virtual Awards Event - University of Virginia - February 4th, 2021
- Nanostructure of the Anodic and Nanomaterials Sol-Gel Based Materials Application: Advances in Surface Engineering - Products Finishing Magazine - December 19th, 2020
- Evelyn Hu delivers 2020 Dresselhaus Lecture on leveraging defects at the nanoscale - MIT News - December 19th, 2020
- COVID-19 airborne transmission research suggests potential therapies | University of Hawaii System News - UH System Current News - December 19th, 2020
- Engineers awarded for ongoing research excellence - News - The University of Sydney - December 19th, 2020
- New Horizons for research through new adventurous research projects - The University of Manchester - December 19th, 2020
- New collaboration provides opportunity for future water scientists and engineers - Cranfield University - December 19th, 2020
- First of its kind at U of T: MIE launches specialized course in 3D printing - U of T Engineering News - December 19th, 2020
- How Integrated Operations is Using a Breakthrough Misting Technology to Stop the Spread of Deadly Viruses and Bacteria - Iosco County News Herald - October 30th, 2020
- Senior Research Assistant in Experimental Condensed Matter Physics job with THE UNIVERSITY OF HONG KONG | 230871 - Times Higher Education (THE) - October 30th, 2020
- Small Satellite Market Size to Hit USD 9.75 Billion by 2027; Presence of Several Large Scale Companies will have a Positive Impact on Market Growth,... - October 30th, 2020
- Impact Of Covid 19 On 3D Print Materials Industry 2020 Market Challenges, Business Overview And Forecast Research Study 2026 - The Think Curiouser - October 30th, 2020
- The U.S. Finally Has a Sputnik Moment With China - Foreign Policy - October 30th, 2020
- Medtronic Announces Adaptix Interbody System, the First Navigated Titanium Cage with Titan nanoLOCK Surface Technology - BioSpace - October 10th, 2020
- Nanocoolant Alternative for Cooling Elements by UMP Researchers - QS WOW News - October 10th, 2020
- Post Pandemic Nano Gas Sensor Market Size to Reach USD XX Million Billion by 2027 Analysis by Top Manufacturers Raytheon Company, Ball Aerospace and... - October 10th, 2020
- IISc Bengaluru researchers discover nanomotors can lead to early detection of cancer cells - The Indian Express - October 10th, 2020