Active notch protects MAPK activated melanoma cell lines from MEK inhibitor cobimetinib.

Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie
Letizia PorcelliAmalia Azzariti

Abstract

The crosstalk between Notch and MAPK pathway plays a role in MEK inhibitor resistance in BRAFV600E metastatic melanoma (MM) and promotes migration in GNAQQ209L uveal melanoma (UM) cells. We determined the cytotoxicity of combinatorial inhibition of MEK and Notch by cobimetinib and γ-secretase inhibitor (GSI) nirogacestat, in BRAFV600E and BRAF wt MM and GNAQQ209L UM cells displaying different Erk1/2 and Notch activation status, with the aim to elucidate the impact of Notch signaling in the response to MEK inhibitor. Overall the combination was synergic in BRAFV600E MM and GNAQQ209L UM cells and antagonistic in BRAF wt one. Focusing on UM cells, we found that cobimetinib resulted in G0/G1 phase arrest and apoptosis induction, whereas the combination with GSI increased treatment efficacy by inducing a senescent-like state of cells and by blocking migration towards liver cancer cells. Mechanistically, this was reflected in a strong reduction of cyclin D1, in the inactivation of retinoblastoma protein and in the increase of p27KIP1 expression levels. Of note, each drug alone prevented Notch signaling activation resulting in inhibition of c-jun(Ser63) and Hes-1 expression. The combination achieved the strongest inhibition on Notch s...Continue Reading

References

Apr 30, 1999·Science·S Artavanis-TsakonasR J Lake
Jun 7, 2000·Pigment Cell Research·R Buscà, R Ballotti
Sep 12, 2000·Oncogene·K FitzgeraldP Leder
Dec 21, 2005·International Ophthalmology Clinics·Agop Y Bedikian
Aug 23, 2008·Investigative Ophthalmology & Visual Science·Michael D OnkenJ William Harbour
Oct 18, 2008·The Journal of Investigative Dermatology·Masatake Osawa, David E Fisher
Dec 17, 2008·Nature·Catherine D Van RaamsdonkBoris C Bastian
Jun 25, 2009·Cancer Research·Chelsea C PinnixMeenhard Herlyn
Jul 6, 2010·Biochimica Et Biophysica Acta·Zhiwei WangFazlul H Sarkar
Nov 19, 2010·The New England Journal of Medicine·Catherine D Van RaamsdonkBoris C Bastian
Feb 16, 2011·The Journal of Cell Biology·Francis Rodier, Judith Campisi
Apr 22, 2011·Nature Reviews. Cancer·Prathibha RanganathanAnthony J Capobianco
Jul 29, 2011·International Journal of Cancer. Journal International Du Cancer·Francesco DituriGianluigi Giannelli
Jan 10, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Laura AsnaghiCharles G Eberhart
Dec 6, 2012·Investigative Ophthalmology & Visual Science·Laura AsnaghiCharles G Eberhart
May 4, 2013·Nature Reviews. Cancer·Morgan O'HayreJ Silvio Gutkind
Jan 7, 2014·PloS One·Isabelle TremblayMarie-Josée Boucher
Oct 12, 2014·Melanoma Research·Alexander N Shoushtari, Richard D Carvajal
Jan 9, 2016·Current Oncology Reports·Romany A N JohnpulleJeffrey A Sosman
Oct 21, 2016·Nature Reviews. Molecular Cell Biology·Sarah J Bray
Sep 23, 2016·Oncotarget·Clemens KreplerJessie Villanueva
Jan 24, 2017·The Journal of Investigative Dermatology·Ayman GradaVincent Falanga
Jun 19, 2017·International Journal of Pharmaceutics·Rosa Maria IacobazziNunzio Denora
Feb 22, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Luca TamagnoneMichael Rehman
Mar 3, 2018·Therapeutic Advances in Medical Oncology·Jessica YangRichard D Carvajal
May 9, 2018·Pigment Cell & Melanoma Research·John J ParkHelen Rizos
Aug 1, 2018·Trends in Cell Biology·Shom GoelJean J Zhao
Sep 12, 2018·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Theresa SteebCarola Berking
Feb 2, 2019·Oncogene·Yoshihiro NishikawaHiroshi Seno
Jul 28, 2019·Cancers·Timo E Schank, Jessica C Hassel

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell Migration

Cell migration is involved in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. Here is the latest research.

Related Papers

Biochimica Et Biophysica Acta
Shanchun GuoRuben R Gonzalez-Perez
Thyroid : Official Journal of the American Thyroid Association
Florian TraversiRoch-Philippe Charles
© 2021 Meta ULC. All rights reserved