puc-header

Melanoma Therapeutic Strategies That Select Against Resistance by Exploiting MYC-Driven Evolutionary Convergence

79 Pages Posted: 6 Apr 2018 Sneak Peek Status: Published

See all articles by Katherine R. Singleton

Katherine R. Singleton

Duke University - Department of Pharmacology and Cancer Biology

Lorin Crawford

Duke University - Department of Statistical Science

Elizabeth Tsu

Duke University - Department of Pharmacology and Cancer Biology

Haley E. Manchester

Harvard University, Harvard Medical School, Brigham and Women's Hospital, Department of Medicine, Genetics Division; Harvard University - Harvard Medical School

Ophelia Maertens

Harvard University, Harvard Medical School, Brigham and Women's Hospital, Department of Medicine, Genetics Division; Harvard University - Harvard Medical School

Xiaojing Liu

Duke University - Department of Pharmacology and Cancer Biology

Maria V. Liberti

Duke University - Department of Pharmacology and Cancer Biology; Cornell University, Department of Molecular Biology and Genetics

Anniefer N. Magpusao

Case Western Reserve University, School of Medicine, Department of Genetics and Genome Sciences

Elizabeth M. Stein

Duke University - Department of Pharmacology and Cancer Biology

Jennifer P. Tingley

Duke University - Department of Pharmacology and Cancer Biology

Dennie T. Frederick

Harvard University - Harvard Medical School; Harvard University - Cancer Center

Genevieve M. Boland

Harvard University - Harvard Medical School; Harvard University - Cancer Center

Keith T. Flaherty

Harvard University - Harvard Medical School; Massachusetts General Hospital, Cancer Center

Shannon J. McCall

Duke University, School of Medicine, Department of Pathology

Clemens Krepler

University of Pennsylvania, The Wistar Institute of Anatomy and Biology, Molecular and Cellular Oncogenesis Program

Katrin Sproesser

University of Pennsylvania, The Wistar Institute of Anatomy and Biology, Molecular and Cellular Oncogenesis Program

Meenhard Herlyn

University of Pennsylvania, The Wistar Institute of Anatomy and Biology, Molecular and Cellular Oncogenesis Program

Drew J. Adams

Case Western Reserve University, School of Medicine, Department of Genetics and Genome Sciences

Jason W. Locasale

Duke University - Department of Pharmacology and Cancer Biology

Karen Cichowski

Harvard University, Harvard Medical School, Brigham and Women's Hospital, Department of Medicine, Genetics Division; Harvard University - Harvard Medical School; Harvard University, Harvard Medical School, Ludwig Center

Sayan Mukherjee

Duke University - Department of Statistical Science; Duke University, Trinity College of Arts & Sciences, Department of Mathematics

Kris C. Wood

Duke University - Department of Pharmacology and Cancer Biology

More...

Abstract

Diverse pathways can drive resistance to BRAF and MEK inhibitors in BRAF mutant melanoma, suggesting that durable control of resistance will be a major challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of over 20 distinct in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following initial drug treatment, then rebounded during tumor progression independent of the upstream pathway driving resistance. Critically, MYC activation was both necessary and sufficient for resistance, and consequently, suppression of MYC activity using either genetic approaches or BET bromodomain inhibition was sufficient to both resensitize diverse BRAFi-resistant models and delay resistance in treatment naïve models. Finally, MYC-driven, BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, including SRC family and c-KIT tyrosine kinases as well as glucose, glutamine, and serine metabolic pathways. Together, these insights enable the rational design of combination therapies that uniquely select against resistance evolution.

Suggested Citation

Singleton, Katherine R. and Crawford, Lorin and Tsu, Elizabeth and Manchester, Haley E. and Maertens, Ophelia and Liu, Xiaojing and Liberti, Maria V. and Magpusao, Anniefer N. and Stein, Elizabeth M. and Tingley, Jennifer P. and Frederick, Dennie T. and Boland, Genevieve M. and Flaherty, Keith T. and McCall, Shannon J. and Krepler, Clemens and Sproesser, Katrin and Herlyn, Meenhard and Adams, Drew J. and Locasale, Jason W. and Cichowski, Karen and Mukherjee, Sayan and Wood, Kris C., Melanoma Therapeutic Strategies That Select Against Resistance by Exploiting MYC-Driven Evolutionary Convergence (2018). Available at SSRN: https://ssrn.com/abstract=3155589 or http://dx.doi.org/10.2139/ssrn.3155589
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Katherine R. Singleton

Duke University - Department of Pharmacology and Cancer Biology

100 Fuqua Drive
Durham, NC 27708-0204
United States

Lorin Crawford

Duke University - Department of Statistical Science

Box 90251
Durham, NC 27708-0251
United States

Elizabeth Tsu

Duke University - Department of Pharmacology and Cancer Biology

100 Fuqua Drive
Durham, NC 27708-0204
United States

Haley E. Manchester

Harvard University, Harvard Medical School, Brigham and Women's Hospital, Department of Medicine, Genetics Division

Boston, MA 02115
United States

Harvard University - Harvard Medical School

25 Shattuck St
Boston, MA 02115
United States

Ophelia Maertens

Harvard University, Harvard Medical School, Brigham and Women's Hospital, Department of Medicine, Genetics Division

Boston, MA 02115
United States

Harvard University - Harvard Medical School

25 Shattuck St
Boston, MA 02115
United States

Xiaojing Liu

Duke University - Department of Pharmacology and Cancer Biology

100 Fuqua Drive
Durham, NC 27708-0204
United States

Maria V. Liberti

Duke University - Department of Pharmacology and Cancer Biology

100 Fuqua Drive
Durham, NC 27708-0204
United States

Cornell University, Department of Molecular Biology and Genetics

Ithaca, NY
United States

Anniefer N. Magpusao

Case Western Reserve University, School of Medicine, Department of Genetics and Genome Sciences

2511 Overlook Road
Cleveland Heights, OH
United States

Elizabeth M. Stein

Duke University - Department of Pharmacology and Cancer Biology

100 Fuqua Drive
Durham, NC 27708-0204
United States

Jennifer P. Tingley

Duke University - Department of Pharmacology and Cancer Biology

100 Fuqua Drive
Durham, NC 27708-0204
United States

Dennie T. Frederick

Harvard University - Harvard Medical School

25 Shattuck St
Boston, MA 02115
United States

Harvard University - Cancer Center

Boston, MA 02114
United States

Genevieve M. Boland

Harvard University - Harvard Medical School

25 Shattuck St
Boston, MA 02115
United States

Harvard University - Cancer Center

Boston, MA 02114
United States

Keith T. Flaherty

Harvard University - Harvard Medical School

25 Shattuck St
Boston, MA 02115
United States

Massachusetts General Hospital, Cancer Center

Boston, MA 02114
United States

Shannon J. McCall

Duke University, School of Medicine, Department of Pathology

Durham, NC
United States

Clemens Krepler

University of Pennsylvania, The Wistar Institute of Anatomy and Biology, Molecular and Cellular Oncogenesis Program

3601 Spruce Street
Philadelphia, PA
United States

Katrin Sproesser

University of Pennsylvania, The Wistar Institute of Anatomy and Biology, Molecular and Cellular Oncogenesis Program

3601 Spruce Street
Philadelphia, PA
United States

Meenhard Herlyn

University of Pennsylvania, The Wistar Institute of Anatomy and Biology, Molecular and Cellular Oncogenesis Program

3601 Spruce Street
Philadelphia, PA
United States

Drew J. Adams

Case Western Reserve University, School of Medicine, Department of Genetics and Genome Sciences

2511 Overlook Road
Cleveland Heights, OH
United States

Jason W. Locasale

Duke University - Department of Pharmacology and Cancer Biology ( email )

100 Fuqua Drive
Durham, NC 27708-0204
United States

Karen Cichowski

Harvard University, Harvard Medical School, Brigham and Women's Hospital, Department of Medicine, Genetics Division

Boston, MA 02115
United States

Harvard University - Harvard Medical School

25 Shattuck St
Boston, MA 02115
United States

Harvard University, Harvard Medical School, Ludwig Center

200 Longwood Avenue
Boston, MA
United States

Sayan Mukherjee

Duke University - Department of Statistical Science

Box 90251
Durham, NC 27708-0251
United States

Duke University, Trinity College of Arts & Sciences, Department of Mathematics

Durham, NC
United States

Kris C. Wood (Contact Author)

Duke University - Department of Pharmacology and Cancer Biology ( email )

100 Fuqua Drive
Durham, NC 27708-0204
United States

Click here to go to Cell.com

Go to Cell.com

Paper statistics

Abstract Views
128
Downloads
4