Restraining Network Response to Targeted Cancer Therapies Improves Efficacy and Reduces Cellular Resistance

Cancer Research
Tirtha K DasRoss L Cagan

Abstract

A key tool of cancer therapy has been targeted inhibition of oncogene-addicted pathways. However, efficacy has been limited by progressive emergence of resistance as transformed cells adapt. Here, we use Drosophila to dissect response to targeted therapies. Treatment with a range of kinase inhibitors led to hyperactivation of overall cellular networks, resulting in emergent resistance and expression of stem cell markers, including Sox2. Genetic and drug screens revealed that inhibitors of histone deacetylases, proteasome, and Hsp90 family of proteins restrained this network hyperactivation. These "network brake" cocktails, used as adjuncts, prevented emergent resistance and promoted cell death at subtherapeutic doses. Our results highlight a general response of cells, transformed and normal, to targeted therapies that leads to resistance and toxicity. Pairing targeted therapeutics with subtherapeutic doses of broad-acting "network brake" drugs may provide a means of extending therapeutic utility while reducing whole body toxicity.Significance: These findings with a strong therapeutic potential provide an innovative approach of identifying effective combination treatments for cancer. Cancer Res; 78(15); 4344-59. ©2018 AACR.

References

Apr 1, 1995·Cancer Genetics and Cytogenetics·L D CooleyR F Gagel
Nov 2, 2001·Nature·T ReyaI L Weissman
Jun 21, 2005·Genetics·Renee D ReadRoss L Cagan
Jul 15, 2005·The New England Journal of Medicine·Frances A ShepherdUNKNOWN National Cancer Institute of Canada Clinical Trials Group
Mar 2, 2006·Journal of the National Cancer Institute·Francesca CarlomagnoMassimo Santoro
Mar 15, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Giuliana SalvatoreMassimo Santoro
Jul 28, 2006·Cold Spring Harbor Symposia on Quantitative Biology·D A HaberJ Settleman
Aug 22, 2006·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Andrea BezjakUNKNOWN National Cancer Institute of Canada Clinical Trials Group Study BR.21
Sep 27, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Quang T LuongH Phillip Koeffler
Jun 28, 2007·Expert Opinion on Investigational Drugs·Madeleine Duvic, Jenny Vu
Aug 20, 2008·Molecular and Cellular Biology·Deborah A Greer CardTrevor K Archer
Nov 26, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Samuel A Wells, Massimo Santoro
Jun 29, 2010·Thyroid : Official Journal of the American Thyroid Association·Tirtha Das, Ross Cagan
May 6, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Sama F SleimanRajiv R Ratan
Sep 29, 2011·Cellular Signalling·Lene Melsæther GrøvdalBo van Deurs
Nov 24, 2011·Endocrine-related Cancer·Yoon Woo KohMatthew D Ringel
Mar 15, 2012·Journal of Hepatology·Marie-José Blivet-Van EggelpoëlChristèle Desbois-Mouthon
Mar 20, 2012·Cell·Michael S Glickman, Charles L Sawyers
Jun 6, 2012·The New England Journal of Medicine·Keith T FlahertyUNKNOWN METRIC Study Group
Jun 15, 2012·Nature Reviews. Cancer·Robert J GilliesRobert A Gatenby
May 15, 2013·Chinese Journal of Cancer·Jing Tan, Qiang Yu
Jul 28, 2013·Investigational New Drugs·Shaji K KumarAlex A Adjei
Sep 26, 2013·Nature Reviews. Cancer·Caitriona HolohanPatrick G Johnston
Apr 22, 2014·Nature Cell Biology·Laetitia SeguinDavid A Cheresh
May 23, 2014·Drug Discovery Today. Technologies·H Eirik Haarberg, Keiran S M Smalley
Jan 22, 2015·Expert Opinion on Pharmacotherapy·Jolanta KrajewskaBarbara Jarzab
Feb 6, 2015·Archives of Pharmacal Research·Pusoon Chun
Mar 10, 2015·Critical Reviews in Oncogenesis·Hong Ping ChenTing C Zhao

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Citations

May 6, 2019·Wiley Interdisciplinary Reviews. Developmental Biology·Tin Tin Su
Jun 20, 2020·Genome Génome / Conseil National De Recherches Canada·Cassandra Millet-BoureimaChiara Gamberi
Aug 23, 2020·International Journal of Molecular Sciences·Helena E RichardsonDaniela Grifoni
Jun 3, 2021·Cell Chemical Biology·Albert A AntolinBissan Al-Lazikani
Nov 9, 2021·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Sonia E SultanDenis Walsh

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