TGFβ2-mediated epithelial-mesenchymal transition and NF-κB pathway activation contribute to osimertinib resistance.

Acta Pharmacologica Sinica
Xiao-Ming JiangJin-Jian Lu

Abstract

Osimertinib (AZD9291) has been widely used for the treatment of EGFR mutant non-small cell lung cancer. However, resistance to osimertinib is inevitable. In this study we elucidated the molecular mechanisms of resistance in osimertinib-resistant NCI-H1975/OSIR cells. We showed that NCI-H1975/OSIR cells underwent epithelial-mesenchymal transition (EMT), which conferred sensitivity to the GPX4 inhibitor 1S, 3R-RSL3 to induce ferroptotic cell death. The EMT occurrence resulted from osimertinib-induced upregulation of TGFβ2 that activated SMAD2. On the other hand, we revealed that NCI-H1975/OSIR cells were highly dependent on NF-κB pathway for survival, since treatment with the NF-κB pathway inhibitor BAY 11-7082 or genetic silence of p65 caused much greater cell death as compared with the parental NCI-H1975 cells. In NCI-H1975 cells, osimertinib activated NF-κB pathway, evidenced by the increased p65 nuclear translocation, which was abolished by knockdown of TGFβ2. In the cancer genome atlas lung adenocarcinoma data, TGFB2 transcript abundance significantly correlated with EMT-associated genes and NF-κB pathway. In addition, coexistence of EMT and activation of NF-κB pathway was observed in several NCI-H1975/OSIR clones. These fin...Continue Reading

References

Jan 1, 1996·Annual Review of Immunology·A S Baldwin
May 1, 2004·Proceedings of the National Academy of Sciences of the United States of America·Tao LuAndrei V Gudkov
Feb 13, 2008·Cell·Matthew S Hayden, Sankar Ghosh
Aug 18, 2010·Proceedings of the National Academy of Sciences of the United States of America·Zhan YaoRaffaella Sordella
Mar 25, 2011·Science Translational Medicine·Lecia V SequistJeffrey A Engelman
Mar 25, 2011·Nature·Trever G BivonaCharles L Sawyers
Jan 22, 2013·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Masakuni SerizawaYasuhiro Koh
Aug 7, 2013·Molecular Cancer·Bastian Hoesel, Johannes A Schmid
Feb 22, 2014·Nature Reviews. Molecular Cell Biology·Samy LamouilleRik Derynck
Oct 1, 2014·British Journal of Cancer·I Vivanco
Mar 12, 2015·Nature Communications·Matthew J NiederstJeffrey A Engelman
Jan 30, 2016·Nature Reviews. Drug Discovery·Fabrizio MarcucciRuggero De Maria
Apr 20, 2016·Proceedings of the National Academy of Sciences of the United States of America·Ching-Feng ChiuJen-Liang Su
Dec 14, 2016·The New England Journal of Medicine·Tony S MokUNKNOWN AURA3 Investigators
Jan 21, 2017·PloS One·Bruno R B PiresEliana S F W Abdelhay
Jul 6, 2017·Nature·Vasanthi S ViswanathanStuart L Schreiber
Jul 19, 2017·Trends in Cancer·Selcuk Colak, Peter Ten Dijke
Nov 2, 2017·Nature·Matthew J HangauerMichael T McManus
Jul 22, 2018·Cancer Research·Cecilia Lopez SambrooksJoseph N Contessa
Sep 20, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Xiuning LeJohn V Heymach
Nov 22, 2018·Nature Reviews. Molecular Cell Biology·Anushka Dongre, Robert A Weinberg
Jan 3, 2019·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Le-Le ZhangJin-Jian Lu
Oct 1, 2019·British Journal of Cancer·Alessandro LeonettiMarcello Tiseo
Nov 22, 2019·The New England Journal of Medicine·Suresh S RamalingamUNKNOWN FLAURA Investigators

❮ Previous
Next ❯

Methods Mentioned

BETA
RNA-seq
PCR
flow cytometry
enzyme-linked immunosorbent assay
ELISA
nuclear translocation
antisense oligonucleotides

Software Mentioned

Gene Set Enrichment Analysis ( GSEA )
Partek
Partek Genomics Suite
FlowJo VX
GSEA
MeV
GraphPad Prism
STAR

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.