Overview

Welcome! We study members of the TAM-family of receptor tyrosine kinases (TYRO3, AXL, and MERTK) in cancer and the effects of TAM inhibition asa disease treatment.

The receptor tyrosine kinase MERTK was first discovered by Dr. Graham and subsequent work in the Graham lab demonstrated oncogenic roles for MERTK in a variety of solid tumor and hematologic malignancies. Current projects focused on acute leukemia, non-small cell lung cancer and melanoma are aimed at better understanding the biology of MERTK and related receptors in tumor cells and their roles in the human immune system. In addition, we developed and characterized a series of novel small molecules that selectively and potently inhibit MERTK with the goal of targeting MERTK to treat patients with cancer. The lead compound, MRX-2843, is a first-in-class dual MERTK and FLT3-selective tyrosine kinase inhibitor that is currently being tested in phase I clinical trials. Studies to determine the optimal application of MERTK inhibitors in combination with other agents to maximize therapeutic effects are ongoing. We are also working with collaborators to develop additional classes of novel inhibitors targeting the TAM kinases.
 

  • Determine mechanisms of resistance to MERTKinhibition.
  • Identify roles and effects of MERTK inhibition in early thymic precursor acute lymphoblastic leukemia (ETP-ALL).
  • Elucidate molecular pathways that can be targeted in combination with MERTK inhibition to enhance therapeutic efficacy against acute myeloid leukemia (AML).
  • Determine oncogenic roles for TYRO3 in AML.
  • Develop biomarkers of MERTK inhibition and therapeutic response.
  • Identify tyrosine kinase inhibitors that synergize with MERTK inhibition to suppress tumor growth.
  • Determine roles for MERTK in resistance to third-generation EGFR tyrosine kinase inhibitors in non-small cell lung cancers with activating EGFR mutations.
  • Determine immunomodulatory roles for MERTK in the tumor microenvironment using syngeneic mouse models of leukemia, lung cancer, and breast cancer.
  • Identify immune biomarkers of MERTK inhibition and therapeutic effects.
  • Evaluate roles for MERTK as a mediator of resistance to immune checkpoint blockade.

Development of small molecule TAM kinase inhibitors for treatment of cancer
Xiaodong Wang, Stephen V. Frye, H. Shelton Earp III, and Dmitri Kireev, University of North Carolina – Chapel Hill

Mediators of resistance to MERTK inhibition in acute myeloid leukemia
Jeff Tyner, BEAT AML Project, Oregon Health Sciences University

Therapeutic modeling using patient-derived 3D bone marrow biomimicry cultures 
Nicki Panoskaltsis, Trinity College Dublin
Sakis Mantalaris, Trinity College Dublin

Targeting MERTK in the tumor immune microenvironment
Susan Thomas, Georgia Institute of Technology
Curtis Henry, University of Colorado


Douglas K. Graham, MD, PhD

Undergraduate: Wake Forest University

Graduate Studies: University of North Carolina (MD, PhD)

Post-doctoral: University of Colorado/Children's Hospital Colorado


Deb DeRyckere, PhD

Undergraduate: University of Michigan 

Graduate Studies: University of California- Berkeley 

Post-doctoral: University of Colorado School of Medicine 

deborah.deryckere@emory.edu


Justus Huelse, PhD

Postdoctoral Research Fellow 

PhD, Emory University, 2023

justus.hulse@emory.edu


G. Humber

Research Specialist

BS, University of Alabama, 2022

ghumber@emory.edu


Edward Henderson

Emory Graduate Student, Cancer Biology 

BS, Davidson College, 2018

edward.benton.henderson@emory.edu 


Alejandro de Janon

Georgia Tech/Emory Graduate Student, Bioengineering

MS, Texas A&M University, 2020

BS, Universidad Tecnológica Nacional 2015

adejan4@emory.edu


Aashis Thapa

Emory Graduate Student, Cancer Biology

BA, Reed College, 2015

aashis.thapa@emory.edu


Dan Yan, MD, PhD

Assistant Professor of Pediatrics 

MD, Tongji Medical School, China 

danyan2@emory.edu


Tsz Yau (Jessica) Yeung

Lead Research Specialist

BS, Emory University, 2020

jessica.yeung@emory.edu


Juhye Yim

Emory Graduate Student, Cancer Biology 

MS, Yonsei University 2020

BS, SUNY Fredonia, 2018

jyim28@emory.edu


K.M. Tanim, MS

Emory Graduate Student, Cancer Biology

MS, West Virginia State University

BS, Khulna University

k.m.ahasan.al.tanim@emory.edu

Dawn Barnes, PhD (2016-2021), postdoctoral fellow

Sherri Smart, MD, PhD (2017-2023), pediatric hematology/oncology senior associate

Ryan Summers, MD (2016-2022), pediatric hematology/oncology fellow

Diana Fridlyand, MD (2019-2023), pediatric hematology/oncology senior associate

Katherine Minson, MD (2013-2019), pediatric hematology/oncology fellow, Assistant Professor

Eleana Vasileiadi, MD (2017-2019), visiting scholar, University of Athens School of Medicine, Greece

Kristen Jacobsen, PhD (2009-2018), graduate student, immunology program; postdoctoral fellow

Sheng Zheng, PhD (2014-2016), visiting scholar, Northeast Dianli University, China

Alexandra Sufit (2014-2015), graduate student, Cancer Biology

Lenka Teodorovic, PhD (2013-2015), postdoctoral fellow

Christopher Cummings (2011-2015), graduate student, Medical Scientist Training Program (MSTP)

Alisa Lee Sherick, MD (2010-2015), pediatric hematology/oncology fellow

Sandra Christoph, MD, PhD (2011-2013), postdoctoral fellow

Amy Keating, MD (2003-2013), pediatric hematology/oncology fellow

Jennifer Schlegel (2010-2012), graduate student, Program in Molecular Biology

Justine Migdall (2009-2012), graduate student, Medical Scientist Training Program (MSTP)

Rachel Linger, PhD (2007-2012), postdoctoral fellow

Luis Pessoa-Brandao, PhD (2007-2012), postdoctoral fellow

Kristen Eisenman, MD (2008-2011), pediatric hematology/oncology fellow

Kelly Sawczyn, MD (2004-2007), pediatric hematology/oncology fellow

Dana Salzberg, MD (2002-2006), pediatric hematology/oncology fellow

NCI R01 – Novel TYRO3 inhibitors for treatment of cancer

Eschelman Institute for Innovation – Novel TYRO3 degraders for treatment of cancer

Donaldson Charitable Trust – Targeting MERTK to improve immunotherapeutic response in NSCLC

NCI Lung SPORE – Targeting MERTK to improve outcomes for EGFR-mutated NSCLC

NCI R01 – Development of dual MERTK and AXL inhibitors

DeRyckere D, Huelse JM, Earp SH, Graham DK. (2023). TAM family kinases as therapeutic targets at the interface of cancer and immunity. Nature Reviews Clinical Oncology, 20(11), 755-779.

Kelvin JM, Chimenti ML, Zhang DY, Williams EK, Moore SG, Humber GM, Baxter TA, Birnbaum LA, Qui M, Zecca H, Thapa A, Jain J, Jui NT, Wang X, Fu H, Du Y, Kemp LM, Lam WA, Graham DK, DeRycker D, Dreaden EC. (2023). Development of constitutively synergistic nanoformulations to enhance chemosensitivity in T-cell leukemia. Journal of controlled release : official journal of the Controlled Release Society, 361, 470–482.

Yan, D, Huelse, HM, Kireev D, Tan Z, Chen L, Goyal S, Wang X, Frye SV, Behera M, Schneider F, Ramalingam SS, Owonikoko T, Earp HS, DeRyckere D, Graham DK. (2022). MERTK activation drives osimertinib resistance in EGFR-mutant non–small cell lung cancer. The Journal of Clinical Investigation, 132(15).

Summers RJ, Jain J, Vasileiadi E, Smith B, Chimenti ML, Yeung TY, Kelvin J, Wang X, Frye SV, Earp HS, Tyner JW, Dreaden EC, DeRyckere D, Graham DK. (2022). Therapeutic targeting of MERTK and BCL-2 in T-cell and early T-precursor acute lymphoblastic leukemia. Cancers, 14(24), 6142.

Sinik L, Minson KA, Tentler JJ, Carrico J, Bagby SM, Robinson WA, Kami R, Burstyn-Cohen T, Eckhardt SG, Wang X, Frye SV, Earp HS, DeRyckere D, Graham DK. (2019). Inhibition of MERTK promotes suppression of tumor growth in BRAF mutant and BRAF wild-type melanoma. Molecular cancer therapeutics, 18(2), 278-288.

Lee-Sherick AB, Jacobsen KM, Henry CJ, Huey MG, Parker RE, Page LS, Hill AA, Wang X, Frye SV, Earp HS, Jordan CT, DeRyckere D, Graham DK. (2018). MERTK inhibition alters the PD-1 axis and promotes anti-leukemia immunity. JCI insight, 3(21).

Minson KA, Smith CC, DeRyckere D, Libbrecht L, Lee-Sherick AB, Huey MG, Lasater EA, Kirkpatrick GD, Stashko MA, Zhang W, Jordan CT, Kireev D, Wang X, Frye SV, Earp HS, Shah NP, Graham DK. (2016). The MERTK/FLT3 inhibitor MRX-2843 overcomes resistance-conferring FLT3 mutations in acute myeloid leukemia. JCI insight, 1(3).

DeRyckere D, Lee-Sherick AB, Huey M, Hill AA, Tyner JW, Jacobsen KM, Page LS, Kirkpatrick GG, Eryildiz F, Montgomery SA, Zhang W, Wang X, Frye SV, Earp HS, Graham DK. (2017). UNC2025, a MERTK small-molecule inhibitor, is therapeutically effective alone and in combination with methotrexate in leukemia models. Clinical Cancer Research, 23(6), 1481-1492.

 

View more publications