Combined Pan-RAF and MEK Inhibition Overcomes Multiple Resistance Mechanisms to Selective RAF Inhibitors

Molecular Cancer Therapeutics
Steven R WhittakerLevi A Garraway

Abstract

RAF and MEK inhibitors are effective in BRAF-mutant melanoma but not in BRAF-mutant colorectal cancer. To gain additional insights into this difference, we performed a genome-scale pooled shRNA enhancer screen in a BRAF-mutant, RAF inhibitor-resistant colorectal cancer cell line exposed to the selective RAF inhibitor PLX4720. We identified multiple genes along the receptor tyrosine kinase (RTK)/mitogen-activated protein kinase (MAPK) signaling axis that, when suppressed, either genetically or pharmacologically, sensitized cells to the selective RAF inhibitor through sustained inhibition of MAPK signaling. Strikingly, CRAF was a key mediator of resistance that could be overcome by the use of pan-RAF inhibitors in combination with a MEK inhibitor. Furthermore, the combination of pan-RAF and MEK inhibitors displayed strong synergy in melanoma and colorectal cancer cell lines with RAS-activating events such as RTK activation, KRAS mutation, or NF1 loss-of-function mutations. Combinations of selective RAF inhibitors, such as PLX4720 or dabrafenib, with MEK inhibitors did not incur such profound synergy, suggesting that inhibition of CRAF by pan-RAF inhibitors plays a key role in determining cellular response. Importantly, in contras...Continue Reading

References

Feb 3, 2005·Nature Reviews. Drug Discovery·Curtis T KeithBrent R Stockwell
May 24, 2006·Molecular Pharmacology·Liwei ChenJie Wu
Feb 22, 2008·Proceedings of the National Academy of Sciences of the United States of America·James TsaiGideon Bollag
May 16, 2008·Proceedings of the National Academy of Sciences of the United States of America·Klaus HellmuthWalter Birchmeier
Jun 19, 2008·Cancer Research·Clara MontagutJeffrey Settleman
Dec 19, 2008·Proceedings of the National Academy of Sciences of the United States of America·Biao LuoDavid E Root
Nov 17, 2009·Proceedings of the National Academy of Sciences of the United States of America·Caroline M EmeryLevi A Garraway
Mar 27, 2010·Current Pharmaceutical Design·Latanya M ScottJie Wu
Jun 12, 2010·Science Translational Medicine·Steven WhittakerRichard Marais
Oct 26, 2010·Trends in Biochemical Sciences·Susan S Taylor, Alexandr P Kornev
Nov 26, 2010·Nature·Cory M JohannessenLevi A Garraway
Jan 20, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Aidan G GilmartinSylvie G Laquerre
Mar 9, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Nikhil WagleLevi A Garraway
Jun 7, 2011·The New England Journal of Medicine·Paul B ChapmanUNKNOWN BRIM-3 Study Group
Jul 13, 2011·Proceedings of the National Academy of Sciences of the United States of America·Hiu Wing CheungWilliam C Hahn
Feb 22, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Yingjun SuAnn Richmond
Jan 5, 2013·Cancer Discovery·Steven R WhittakerLevi A Garraway
May 18, 2013·Cancer Cell·Matthew HolderfieldTobi E Nagel
Sep 3, 2013·Cell·Jiancheng HuAndrey S Shaw
Nov 10, 2013·Nature Medicine·Piro LitoDavid B Solit
Apr 29, 2014·Cancer Discovery·David J KonieczkowskiLevi A Garraway
Sep 10, 2014·Cell Reports·Simona LambaAlberto Bardelli
Jan 16, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Rona YaegerLeonard B Saltz

❮ Previous
Next ❯

Citations

Jun 3, 2016·Expert Review of Molecular Diagnostics·Loren Joseph
Jun 25, 2016·Seminars in Cell & Developmental Biology·Gajendra ShresthaAndrea H Bild
Jun 24, 2016·British Journal of Cancer·Shivshankari Rajkumar, Ian R Watson
Jun 28, 2016·Biochimica Et Biophysica Acta·Paulo MatosPeter Jordan
Jan 10, 2019·The Journal of Pharmacology and Experimental Therapeutics·Gautham GampaWilliam F Elmquist
Dec 10, 2019·Current Opinion in Pediatrics·Angelina V Vaseva, Marielle E Yohe
May 27, 2017·Current Pharmacology Reports·Gautham GampaWilliam F Elmquist
Jul 11, 2018·Journal of Experimental & Clinical Cancer Research : CR·Anais Del CuratoloLudovica Ciuffreda
Jun 12, 2019·Nature Communications·Greg G JonesPablo Rodriguez-Viciana
Sep 30, 2016·Neuro-oncology·Roger J PackerMark Kieran
Oct 24, 2018·Proceedings of the National Academy of Sciences of the United States of America·Lucy C YoungPablo Rodriguez-Viciana
Sep 17, 2016·Angewandte Chemie·Brice SautierLars Wortmann
Dec 3, 2016·Biochemical Society Transactions·Ana HerreroWalter Kolch
Jan 15, 2019·Cancer Cell International·Marta Llaurado FernandezMark S Carey
Nov 13, 2019·Nature Reviews. Drug Discovery·Alan HuangBarbara Weber
May 27, 2020·American Society of Clinical Oncology Educational Book·Ozge GumusayHope S Rugo
Feb 13, 2018·Cancer Discovery·Ryan B CorcoranEric Van Cutsem
Jun 29, 2017·Molecular Cancer Research : MCR·Caroline M EmeryGiordano Caponigro
Nov 21, 2019·Molecular Cancer Therapeutics·Shripad V BhagwatSheng-Bin Peng
Oct 9, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Alex PearsonNicholas C Turner
Feb 9, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Wenhao WengAjay Goel
Apr 24, 2020·Anti-cancer Agents in Medicinal Chemistry·Qing-Shan LiBan-Feng Ruan
Feb 3, 2021·Molecular and Cellular Biology·Jason J Kwon, William C Hahn

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.

CREs: Gene & Cell Therapy

Gene and cell therapy advances have shown promising outcomes for several diseases. The role of cis-regulatory elements (CREs) is crucial in the design of gene therapy vectors. Here is the latest research on CREs in gene and cell therapy.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Cell Signaling by Tyrosine Kinases

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. RTKs have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Discover the latest research on cell signaling and RTK here.