Combined targeting of G protein-coupled receptor and EGF receptor signaling overcomes resistance to PI3K pathway inhibitors in PTEN-null triple negative breast cancer.

EMBO Molecular Medicine
Davide ZecchinJulian Downward

Abstract

Triple-negative breast cancer (TNBC) has poorer prognosis compared to other types of breast cancers due to the lack of effective therapies and markers for patient stratification. Loss of PTEN tumor suppressor gene expression is a frequent event in TNBC, resulting in over-activation of the PI 3-kinase (PI3K) pathway and sensitivity to its inhibition. However, PI3K pathway inhibitors show limited efficacy as monotherapies on these tumors. We report a whole-genome screen to identify targets whose inhibition enhanced the effects of different PI3K pathway inhibitors on PTEN-null TNBC. This identified a signaling network that relies on both the G protein-coupled receptor for thrombin (PAR1/F2R) and downstream G protein βγ subunits and also epidermal growth factor receptor (EGFR) for the activation of the PI3K isoform p110β and AKT. Compensation mechanisms involving these two branches of the pathway could bypass PI3K blockade, but combination targeting of both EGFR and PI3Kβ suppressed ribosomal protein S6 phosphorylation and exerted anti-tumor activity both in vitro and in vivo, suggesting a new potential therapeutic strategy for PTEN-null TNBC.

References

Oct 23, 1997·Nucleic Acids Research·K U WagnerL Hennighausen
Feb 18, 2004·Molecular and Cellular Biology·Michelle A BoodenJoAnn Trejo
Feb 5, 2005·Breast Cancer Research and Treatment·Gunter von MinckwitzAndreas Schneeweiss
Apr 9, 2005·Cell Death and Differentiation·G Di MairaM Ruzzene
Jun 2, 2006·The Journal of Pathology·J S Reis-FilhoF C Schmitt
Jun 17, 2006·Genes & Development·Mei-Ling ChenNissim Hay
Jan 4, 2008·Histopathology·J S Reis-Filho, A N J Tutt
Feb 6, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Cornelia LiedtkeLajos Pusztai
Aug 5, 2008·Cancer Research·Katherine Stemke-HaleBryan T Hennessy
Aug 30, 2008·Proceedings of the National Academy of Sciences of the United States of America·Susan WeeChristoph Lengauer
Dec 3, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Maura N DicklerClifford A Hudis
May 20, 2009·Bioinformatics·Heng Li, Richard Durbin
Jul 4, 2009·Cancer Cell·Krishna M VasudevanLevi A Garraway
Nov 10, 2010·Breast Cancer Research : BCR·Reinaldo D Chacón, María V Costanzo
Dec 16, 2010·Cancer Genetics and Cytogenetics·Berrak GumuskayaGulnur Guler
Dec 14, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Johanna C BendellJosé Baselga
Jun 6, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Lisa A CareyEric P Winer
Aug 31, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Takafumi SangaiFunda Meric-Bernstam
Sep 25, 2012·Nature·UNKNOWN Cancer Genome Atlas Network
Jan 11, 2014·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Heae Surng ParkSo Yeon Park
Jan 24, 2014·The New England Journal of Medicine·Richard R FurmanSusan M O'Brien
Jan 24, 2014·The New England Journal of Medicine·Ajay K GopalGilles A Salles
Apr 17, 2014·Proceedings of the National Academy of Sciences of the United States of America·Fabienne SchmitJean J Zhao
Dec 24, 2014·Nature Reviews. Cancer·Lauren M ThorpeJean J Zhao
Oct 19, 2016·Nature Reviews. Clinical Oncology·Giampaolo BianchiniLuca Gianni
Nov 3, 2016·Annals of Oncology : Official Journal of the European Society for Medical Oncology·M MartínS Delaloge

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Citations

Mar 20, 2021·The Biochemical Journal·Silvia ArcucciJulie Guillermet-Guibert
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Eleanor L AtkinsonDavid R Spring

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Methods Mentioned

BETA
RNAseq
xenografts
xenograft
protein array
genetic modifications
PCR
Assay
protein assay
electrophoresis
Infrared Imaging

Software Mentioned

Cellomics ArrayScan VTI
ImageLite
house
bwa
ImageStudioLite
Access
Chalice Analyser

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